Publications by authors named "Mark T Hamann"

133 Publications

RSK1 vs. RSK2 Inhibitory Activity of the Marine β-Carboline Alkaloid Manzamine A: A Biochemical, Cervical Cancer Protein Expression, and Computational Study.

Mar Drugs 2021 Sep 7;19(9). Epub 2021 Sep 7.

Department of Drug Discovery and Biomedical Sciences and Public Health, Colleges of Pharmacy and Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.

Manzamines are complex polycyclic marine-derived β-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia, and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, SIX1, and vacuolar ATPases. We hypothesized that additional, yet undiscovered molecular targets might be associated with Manzamine A's (MZA) reported pharmacological properties. We report here, for the first time, that MZA selectively inhibited a 90 kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases, while in vitro RSK kinase assays demonstrated a 10-fold selectivity in the potency of MZA against RSK1 versus RSK2. The effect of MZA on inhibiting cellular RSK1 and RSK2 protein expression was validated in SiHa and CaSki human cervical carcinoma cell lines. MZA's differential binding and selectivity toward the two isoforms was also supported by computational docking experiments. Specifically, the RSK1-MZA (N- and C-termini) complexes appear to have stronger interactions and preferable energetics contrary to the RSK2-MZA ones. In addition, our computational strategy suggests that MZA binds to the N-terminal kinase domain of RSK1 rather than the C-terminal domain. RSK is a vertebrate family of cytosolic serine-threonine kinases that act downstream of the ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes, including growth, survival, and proliferation. Consequently, our findings have led us to hypothesize that MZA and the currently known manzamine-type alkaloids isolated from several sponge genera may have novel pharmacological properties with unique molecular targets, and MZA provides a new tool for chemical-biology studies involving RSK1.
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http://dx.doi.org/10.3390/md19090506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467814PMC
September 2021

Forrestiacids A and B, Pentaterpene Inhibitors of ACL and Lipogenesis: Extending the Limits of Computational NMR Methods in the Structure Assignment of Complex Natural Products.

Angew Chem Int Ed Engl 2021 10 2;60(41):22270-22275. Epub 2021 Sep 2.

School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China.

Forrestiacids A (1) and B (2) are a novel class of [4+2] type pentaterpenoids derived from a rearranged lanostane moiety (dienophile) and an abietane unit (diene). These unprecedented molecules were isolated using guidance by molecular ion networking (MoIN) from Pseudotsuga forrestii, an endangered member of the Asian Douglas Fir Family. The intermolecular hetero-Diels-Alder adducts feature an unusual bicyclo[2.2.2]octene ring system. Their structures were elucidated by spectroscopic analysis, GIAO NMR calculations and DP4+ probability analyses, electronic circular dichroism calculations, and X-ray diffraction analysis. This unique addition to the pentaterpene family represents the largest and the most complex molecule successfully assigned using computational approaches to predict accurately chemical shift values. Compounds 1 and 2 exhibited potent inhibitory activities (IC s <5 μM) of ATP-citrate lyase (ACL), a new drug target for the treatment of glycolipid metabolic disorders including hyperlipidemia. Validating this activity 1 effectively attenuated the de novo lipogenesis in HepG2 cells. These findings provide a new chemical class for developing potential therapeutic agents for ACL-related diseases with strong links to traditional medicines.
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http://dx.doi.org/10.1002/anie.202109082DOI Listing
October 2021

Hepatoprotective Glucosyloxybenzyl 2-Hydroxy-2-isobutylsuccinates from .

J Nat Prod 2021 03 19;84(3):738-749. Epub 2021 Feb 19.

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425, United States.

Nine new glucosyloxybenzyl 2-hydroxy-2-isobutylsuccinates, pleionosides M-U (-), and 12 known compounds (-) were isolated from the pseudobulbs of . Their structures and absolute configurations were established through a combination of HRESIMS and NMR data and supported by physical and chemical methods. Compounds , , , and showed significant in vitro hepatoprotective activity against d-galactosamine (d-GalN)-induced toxicity in HL-7702 cells with increasing cell viability by 27%, 22%, 19%, and 31% compared to the model group (cf. bicyclol, 14%) at 10 μM, respectively. Compounds , , and exhibited moderate hepatoprotective activity against -acetyl--aminophenol (APAP)-induced toxicity in HepG2 cells with increasing cell viability by 9%, 16%, and 12% compared to the model group (cf. bicyclol, 9%) at 10 μM, respectively.
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http://dx.doi.org/10.1021/acs.jnatprod.0c01117DOI Listing
March 2021

Role of symbiosis in the discovery of novel antibiotics.

J Antibiot (Tokyo) 2020 08 4;73(8):490-503. Epub 2020 Jun 4.

Department of Drug Discovery, Biomedical Sciences and Public Health, College of Pharmacy and Medicine, Medical University of South Carolina, Charleston, SC, USA.

Antibiotic resistance has been an ongoing challenge that has emerged almost immediately after the initial discovery of antibiotics and requires the development of innovative new antibiotics and antibiotic combinations that can effectively mitigate the development of resistance. More than 35,000 people die each year from antibiotic resistant infections in just the United States. This signifies the importance of identifying other alternatives to antibiotics for which resistance has developed. Virtually, all currently used antibiotics can trace their genesis to soil derived bacteria and fungi. The bacteria and fungi involved in symbiosis is an area that still remains widely unexplored for the discovery and development of new antibiotics. This brief review focuses on the challenges and opportunities in the application of symbiotic microbes and also provides an interesting platform that links natural product chemistry with evolutionary biology and ecology.
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http://dx.doi.org/10.1038/s41429-020-0321-6DOI Listing
August 2020

Isolation and Synthesis of Veranamine, an Antidepressant Lead from the Marine Sponge .

J Nat Prod 2020 04 31;83(4):1092-1098. Epub 2020 Mar 31.

Departments of Pharmacognosy and Pharmacology, National Center for Natural Products Research, University of Mississippi, University Park, Mississippi 38677, United States.

The natural product veranamine was isolated from the marine sponge . It contains a unique heterocyclic scaffold and demonstrates in vivo antidepressant activity and selective affinity for 5HT2B and sigma-1 receptors. The first total synthesis of veranamine is reported. Our scalable synthesis offers veranamine in six steps and 25% yield via an unprecedented vinylogous Pictet-Gams pyridine formation strategy. Veranamine is a promising new lead compound for antidepressant drug development.
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http://dx.doi.org/10.1021/acs.jnatprod.9b01107DOI Listing
April 2020

The Marine Natural Product Manzamine A Inhibits Cervical Cancer by Targeting the SIX1 Protein.

J Nat Prod 2020 02 5;83(2):286-295. Epub 2020 Feb 5.

Department of Drug Discovery and Biomedical Sciences , Medical University of South Carolina , Charleston , South Carolina , United States.

Natural products remain an important source of drug leads covering unique chemical space and providing significant therapeutic value for the control of cancer and infectious diseases resistant to current drugs. Here, we determined the antiproliferative activity of a natural product manzamine A () from an Indo-Pacific sponge following various in vitro cellular assays targeting cervical cancer (C33A, HeLa, SiHa, and CaSki). Our data demonstrated the antiproliferative effects of at relatively low and non-cytotoxic concentrations (up to 4 μM). Mechanistic investigations confirmed that blocked cell cycle progression in SiHa and CaSki cells at G1/S phase and regulated cell cycle-related genes, including restoration of p21 and p53 expression. In apoptotic assays, HeLa cells showed the highest sensitivity to as compared to other cell types (C33A, SiHa, and CaSki). Interestingly, decreased the levels of the oncoprotein SIX1, which is associated with oncogenesis in cervical cancer. To further investigate the structure-activity relationship among manzamine A () class with potential antiproliferative activity, molecular networking facilitated the efficient identification, dereplication, and assignment of structures from the manzamine class and revealed the significant potential in the design of optimized molecules for the treatment of cervical cancer. These data suggest that this sponge-derived natural product class warrants further attention regarding the design and development of novel manzamine analogues, which may be efficacious for preventive and therapeutic treatment of cancer. Additionally, this study reveals the significance of protecting fragile marine ecosystems from climate change-induced loss of species diversity.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161578PMC
February 2020

The anti-MRSA compound 3-O-alpha-L-(2″,3″-di-p-coumaroyl)rhamnoside (KCR) inhibits protein synthesis in Staphylococcus aureus.

J Proteomics 2020 01 17;210:103539. Epub 2019 Oct 17.

Henry Ford Health System, Detroit, MI, USA; 21st Century Therapeutics, Detroit, MI 48201, USA.

Methicillin-resistant S aureus (MRSA) contributes to patient mortality and extended hospital stays. 3-O-alpha-L-(2″,3″-di-p-coumaroyl)rhamnoside (KCR) is a natural product antibiotic that is effective against MRSA but has no known mechanism of action (MOA). We used proteomics to identify the MOA for KCR. Methicillin sensitive S aureus and a mixture of four KCR stereoisomers were tested. A time-kill assay was used to choose a 4 h treatment using KCR at 5× its MIC for proteomic analysis. S aureus was treated in triplicate with KCR, oxacillin or vehicle and quantitative proteomic analysis was carried out using isobaric tags and mass spectrometry. 1190 proteins were identified and 552 were affected by KCR (q < 0.01). Ontology analysis identified 6 distinct translation-related categories that were affected by KCR (PIANO, 10% false-discovery rate) including structural constituent of ribosome, translation, rRNA binding, tRNA binding, tRNA processing and aminoacyl-tRNA ligase activity. Median fold changes (KCR vs Control) for small and large ribosomal components were 1.46 and 1.43 respectively. KCR inhibited the production of luciferase protein in an in vitro assay (IC50 39.6 μg/ml). Upregulation of translation-related proteins in response to KCR indicates that KCR acts to disrupt S aureus protein synthesis. This was confirmed with an in vitro transcription/translation assay. SIGNIFICANCE: Methicillin-resistant S aureus (MRSA) contributes to patient mortality and extended hospital stays. 3-O-alpha-L-(2″,3″-di-p-coumaroyl)rhamnoside (KCR) is a natural product antibiotic that is effective against MRSA but has no known mechanism of action (MOA). Using proteomic analysis we determined that KCR acts by inhibiting protein synthesis. KCR is an exciting novel antibiotic and this work represents an important step in its development towards clinical use.
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http://dx.doi.org/10.1016/j.jprot.2019.103539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014561PMC
January 2020

Hepatoprotective Tetrahydrobenzocyclooctabenzofuranone Lignans from .

J Nat Prod 2019 10 26;82(10):2842-2851. Epub 2019 Sep 26.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica , Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 , People's Republic of China.

Three new tetrahydrobenzocyclooctabenzofuranone lignan glucosides, longipedunculatins A-C (-), a new dibenzocyclooctadiene lignan glucoside, longipedunculatin D (), a new dibenzocyclooctadiene lignan (), five new tetrahydrobenzocyclooctabenzofuranone lignans (-), and two new simple lignans (, ) were isolated from the roots of Their structures and absolute configurations were established using a combination of MS, NMR, and experimental and calculated electronic circular dichroism data. Compound showed moderate hepatoprotective activity against -acetyl--aminophenol-induced toxicity in HepG2 cells with a cell survival rate at 10 μM of 50.8%. Compounds , , and showed significant in vitro inhibitory effects with an inhibition rate of 55.1%, 74.9%, and 89.8% on nitric oxide production assays at 10 μM.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00576DOI Listing
October 2019

Marine natural products in the discovery and development of potential pancreatic cancer therapeutics.

Adv Cancer Res 2019 6;144:299-314. Epub 2019 Jun 6.

Departments of Drug Discovery, Biomedical Sciences, and Public Health Sciences, Hollings Cancer Center, College of Pharmacy, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

Pancreatic cancer one of the most deadly cancers and is an increasingly significant concern for global health. The death rates for pancreatic cancer have changed little over time, even with recent expansions of first-line drugs to treat pancreatic cancer there has been little improvement in patient prognosis. Any improvements in treatment strategies will come as a much-needed reprieve to patients diagnosed with this uniquely-challenging disease. Greater attention is needed regarding the identification and development of novel chemotherapeutic strategies with unique mechanisms of action. The marine environment with its particularity has provided a diverse source of novel structural compounds with interesting activities. The marine natural products reported from 2006 to 2018 with compelling activity and potential for the control of pancreatic cancer based on in vitro and in vivo results will be summarized. A key goal of this review is to draw attention to those molecules that warrant additional preclinical development studies.
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http://dx.doi.org/10.1016/bs.acr.2019.05.003DOI Listing
June 2020

Computationally Assisted Discovery and Assignment of a Highly Strained and PANC-1 Selective Alkaloid from Alaska's Deep Ocean.

J Am Chem Soc 2019 03 5;141(10):4338-4344. Epub 2019 Mar 5.

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy , Medical University of South Carolina , Charleston , South Carolina 29425 , United States.

We report here the orchestration of molecular ion networking and a set of computationally assisted structural elucidation approaches in the discovery of a new class of pyrroloiminoquinone alkaloids that possess selective bioactivity against pancreatic cancer cell lines. Aleutianamine represents the first in a new class of pyrroloiminoquinone alkaloids possessing a highly strained multibridged ring system, discovered from Latrunculia ( Latrunculia) austini Samaai, Kelly & Gibbons, 2006 (class Demospongiae, order Poecilosclerida, family Latrunculiidae) recovered during a NOAA deep-water exploration of the Aleutian Islands. The molecule was identified with the guidance of mass spectrometry, nuclear magnetic resonance, and molecular ion networking (MoIN) analysis. The structure of aleutianamine was determined using extensive spectroscopic analysis in conjunction with computationally assisted quantifiable structure elucidation tools. Aleutianamine exhibited potent and selective cytotoxicity toward solid tumor cell lines including pancreatic cancer (PANC-1) with an IC of 25 nM and colon cancer (HCT-116) with an IC of 1 μM, and represents a potent and selective candidate for advanced preclinical studies.
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http://dx.doi.org/10.1021/jacs.8b11403DOI Listing
March 2019

Computationally Assisted Assignment of the Kadsuraols, a Class of Chemopreventive Agents for the Control of Liver Cancer.

Org Lett 2018 09 7;20(18):5559-5563. Epub 2018 Sep 7.

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy , Medical University of South Carolina , Charleston , South Carolina 29425 , United States.

Kadsuraols A-C (1-3), which are tetrahydrocyclobutaphenanthrofuranone-type lignans with a new carbon skeleton comprising a four-membered ring across C-1'-C-8, have been isolated from the roots of Kadsura longipedunculata. Their structures and absolute configurations were unambiguously determined using nuclear magnetic resonance, X-ray diffraction crystallography, DP4+ calculations, and computed and experimental electronic circular dichroism spectra. Kadsuraol C (3) exhibited hepatoprotective activity against N-acetyl- p-aminophenol (APAP)-induced toxicity. The compounds showed no cytotoxicity at 10 μM in a zone assay.
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http://dx.doi.org/10.1021/acs.orglett.8b02207DOI Listing
September 2018

Lemon yellow #15 a new highly stable, water soluble food colorant from the peel of Citrus limon.

Food Chem 2019 Jan 9;270:251-256. Epub 2018 Jul 9.

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address:

To provide stable and low-cost naturally derived yellow pigments, a variety of food byproducts were evaluated and the constituents of lemon peel have emerged yielding a highly promising natural product with applications as a food dye. Here we report a new, highly stable and water soluble food dye called yellow #15 from the ethanol extract of the zest of Citrus limon. The structure of lemon yellow #15 was carefully assigned on the basis of spectroscopic data, including 1D and 2D NMR spectroscopy, and the absolute configuration was established by comparison of the experimental CD with calculated electronic circular dichroism (ECD) spectral data. CIELAB values and Delta CIELAB were measured and revealed this new water-soluble pigment has superior light stability relative to other natural products used as food dyes.
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http://dx.doi.org/10.1016/j.foodchem.2018.07.055DOI Listing
January 2019

Sesterterpenoid and Steroid Metabolites from a Deep-Water Alaska Sponge Inhibit Wnt/β-Catenin Signaling in Colon Cancer Cells.

Mar Drugs 2018 Aug 27;16(9). Epub 2018 Aug 27.

Department of Pharmacognosy, College of Pharmacy, Chungnam National University, Daejeon 34134, Korea.

The Wnt/β-catenin signaling pathway is known to play critical roles in a wide range of cellular processes: cell proliferation, differentiation, migration and embryonic development. Importantly, dysregulation of this pathway is tightly associated with pathogenesis in most human cancers. Therefore, the Wnt/β-catenin pathway has emerged as a promising target in anticancer drug screening programs. In the present study, we have isolated three previously unreported metabolites from an undescribed sponge, a species of (Order Poecilosclerida, Family ), closely related to the northeastern Pacific species , collected from deep waters off the Aleutian Islands of Alaska. Through an assortment of NMR, MS, ECD, computational chemical shifts calculation, and DP4, chemical structures of these metabolites have been characterized as spirocyclic ring-containing sesterterpenoid () and cholestane-type steroidal analogues ( and ). These compounds exhibited the inhibition of β-catenin response transcription (CRT) through the promotion of β-catenin degradation, which was in part implicated in the antiproliferative activity against two CRT-positive colon cancer cell lines.
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http://dx.doi.org/10.3390/md16090297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164309PMC
August 2018

Slow-Binding Inhibition of Mycobacterium tuberculosis Shikimate Kinase by Manzamine Alkaloids.

Biochemistry 2018 08 31;57(32):4923-4933. Epub 2018 Jul 31.

Department of Drug Discovery and Development, Harrison School of Pharmacy , Auburn University , 4306 Walker Building , Auburn , Alabama 36849 , United States.

Tuberculosis represents a significant public health crisis. There is an urgent need for novel molecular scaffolds against this pathogen. We screened a small library of marine-derived compounds against shikimate kinase from Mycobacterium tuberculosis ( MtSK), a promising target for antitubercular drug development. Six manzamines previously shown to be active against M. tuberculosis were characterized as MtSK inhibitors: manzamine A (1), 8-hydroxymanzamine A (2), manzamine E (3), manzamine F (4), 6-deoxymanzamine X (5), and 6-cyclohexamidomanzamine A (6). All six showed mixed noncompetitive inhibition of MtSK. The lowest K values were obtained for 6 across all MtSK-substrate complexes. Time-dependent analyses revealed two-step, slow-binding inhibition. The behavior of 1 was typical; initial formation of an enzyme-inhibitor complex (EI) obeyed an apparent K of ∼30 μM with forward ( k) and reverse ( k) rate constants for isomerization to an EI* complex of 0.18 and 0.08 min, respectively. In contrast, 6 showed a lower K for the initial encounter complex (∼1.5 μM), substantially faster isomerization to EI* ( k = 0.91 min), and slower back conversion of EI* to EI ( k = 0.04 min). Thus, the overall inhibition constants, K*, for 1 and 6 were 10 and 0.06 μM, respectively. These findings were consistent with docking predictions of a favorable binding mode and a second, less tightly bound pose for 6 at MtSK. Our results suggest that manzamines, in particular 6, constitute a new scaffold from which drug candidates with novel mechanisms of action could be designed for the treatment of tuberculosis by targeting MtSK.
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http://dx.doi.org/10.1021/acs.biochem.8b00231DOI Listing
August 2018

Raistrickiones A-E from a Highly Productive Strain of Generated through Thermo Change.

Mar Drugs 2018 Jun 18;16(6). Epub 2018 Jun 18.

College of Pharmacy, Binzhou Medical University, Yantai 264003, China.

Three new diastereomers of polyketides (PKs), raistrickiones A−C (⁻), together with two new analogues, raistrickiones D and E ( and ), were isolated from a highly productive strain of , which was subjected to an experimental thermo-change strategy to tap its potential of producing new secondary metabolites. Metabolites and existed in a diastereomeric mixture in the crystal packing according to the X-ray data, and were laboriously separated by semi-preparative HPLC on a chiral column. The structures of ⁻ were determined on the basis of the detailed analyses of the spectroscopic data (UV, IR, HRESIMS, 1D, and 2D NMR), single-crystal X-ray diffractions, and comparison of the experimental and calculated electronic circular dichroism spectra. Compounds ⁻ represented the first case of 3,5-dihydroxy-4-methylbenzoyl derivatives of natural products. Compounds ⁻ exhibited moderate radical scavenging activities against 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH).
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http://dx.doi.org/10.3390/md16060213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025261PMC
June 2018

A Chemical Investigation of the Leaves of L.

Molecules 2018 04 26;23(5). Epub 2018 Apr 26.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

The leaves of L. are an important herbal medicine in Asia. The systematic isolation of the metabolites of the leaves of L. was achieved using a combination of liquid chromatography techniques. The structures were elucidated by spectroscopic data analysis and the absolute configuration was determined based on electronic circular dichroism (ECD) spectroscopic data and hydrolysis experiments. Their biological activity was evaluated using different biological assays, such as the assessment of their capacity to inhibit the aldose reductase enzyme; the determination of their cytotoxic activity and the evaluation of their neuroprotective effects against the deprivation of serum or against the presence of nicouline. Chemical investigation of the leaves of L. resulted in four new structures ⁻ and a known molecule . Compounds and inhibited aldose reductase with IC values of 4.33 μM and 6.0 μM compared with the potent AR inhibitor epalrestat (IC 1.88 × 10 μM). Pretreatment with compound decreased PC12 cell apoptosis subsequent serum deprivation condition and pretreatment with compound decreased nicouline-induced PC12 cell apoptosis as compared with control cells ( < 0.001).
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http://dx.doi.org/10.3390/molecules23051018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102566PMC
April 2018

Mechanism of irreversible inhibition of Mycobacterium tuberculosis shikimate kinase by ilimaquinone.

Biochim Biophys Acta Proteins Proteom 2018 May - Jun;1866(5-6):731-739. Epub 2018 Apr 12.

Department of Drug Discovery and Development, Harrison School of Pharmacy, 3306 Walker Building, Auburn University, Auburn, AL 36849, USA. Electronic address:

Ilimaquinone (IQ), a marine sponge metabolite, has been considered as a potential therapeutic agent for various diseases due to its broad range of biological activities. We show that IQ irreversibly inactivates Mycobacterium tuberculosis shikimate kinase (MtSK) through covalent modification of the protein. Inactivation occurred with an apparent second-order rate constant of about 60 M s. Following reaction with IQ, LC-MS analyses of intact MtSK revealed covalent modification of MtSK by IQ, with the concomitant loss of a methoxy group, suggesting a Michael-addition mechanism. Evaluation of tryptic fragments of IQ-derivatized MtSK by MS/MS demonstrated that Ser and Thr residues were most frequently modified with lesser involvement of Lys and Tyr. In or near the MtSK active site, three residues of the P-loop (K15, S16, and T17) as well as S77, T111, and S44 showed evidence of IQ-dependent derivatization. Accordingly, inclusion of ATP in IQ reactions with MtSK partially protected the enzyme from inactivation and limited IQ-based derivatization of K15 and S16. Additionally, molecular docking models for MtSK-IQ were generated for IQ-derivatized S77 and T111. In the latter, ATP was observed to sterically clash with the IQ moiety. Out of three other enzymes evaluated, lactate dehydrogenase was derivatized and inactivated by IQ, but pyruvate kinase and catalase-peroxidase (KatG) were unaffected. Together, these data suggest that IQ is promiscuous (though not entirely indiscriminant) in its reactivity. As such, the potential of IQ as a lead in the development of antitubercular agents directed against MtSK or other targets is questionable.
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http://dx.doi.org/10.1016/j.bbapap.2018.04.007DOI Listing
July 2018

Hepatoprotective Dibenzocyclooctadiene and Tetrahydrobenzocyclooctabenzofuranone Lignans from Kadsura longipedunculata.

J Nat Prod 2018 04 29;81(4):846-857. Epub 2018 Mar 29.

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , People's Republic of China.

Five new dibenzocyclooctadiene lignans, longipedlignans A-E (1-5), five new tetrahydrobenzocyclooctabenzofuranones (6-10), and 18 known analogues (11-28) were isolated from the roots of Kadsura longipedunculata. Compounds 6-10 are new spirobenzofuranoid-dibenzocyclooctadiene-type lignans. Their structures and absolute configurations were established using a combination of MS, NMR, and electronic circular dichroism data. Spirobenzofuranoids 6 and 15 showed moderate hepatoprotective activity against N-acetyl- p-aminophenol-induced toxicity in HepG2 cells with cell survival rates at 10 μM of 52.2% and 50.2%, respectively.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00934DOI Listing
April 2018

Assignment of the absolute configuration of hepatoprotective highly oxygenated triterpenoids using X-ray, ECD, NMR J-based configurational analysis and HSQC overlay experiments.

Biochim Biophys Acta Gen Subj 2017 Dec 15;1861(12):3089-3095. Epub 2017 Sep 15.

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, United States. Electronic address:

Background: The plants of the genus Kadsura are widely distributed in China, South Korea, and Japan. Their roots and stems are traditionally used to treat blood diseases and pain. The main bioactive constituents of Kadsura longipedunculata comprise highly oxygenated triterpenoids. Schiartane-type nortriterpenoids showed anti-HIV, anti-HBV, and cytotoxic bioactivities. For such compounds, the absolute configuration influences the bioactivities, and hence its unambiguous determination is essential. In this work, the absolute configurations of three highly oxygenated schiartane-type nortriterpenoids were unequivocally assigned using X-ray, ECD, and J-based configuration analysis and HSQC overlay data.

Methods: The ethanol extract of Kadsura longipedunculata Finet et Gagnep was purified by column chromatography using silica, Sephadex LH-20, and ODS as substrates. To help assign the absolute configuration of schiartane-type nortriterpenoids, X-ray diffraction analysis, ECD experiment compared to ab initio computed data, DP4+ analysis, HSQC overlay, NOESY, and J-based configuration analysis were carried out. Hetero- and homo-nuclear coupling constants were extracted from HETLOC experiments.

Results: Three new highly oxygenated triterpenoids, micrandilactone I (1), micrandilactone J (2), and 22,23-di-epi-micrandilactone J (3) were isolated. Their 2D structures were solved using NMR and HRESIMS data and their absolute configurations were elucidated using X-ray diffraction analysis, ECD experimental results compared to ab initio computed spectra, HSQC overlay, DP4+, NOESY, and J-based configuration analysis. Micrandilactone I (1) and 22,23-di-epi-micrandilactone J (3) showed moderate hepatoprotective activity against APAP-induced toxicity in HepG2 cells with cell survival rates of 53.0 and 50.2%, respectively, at 10μM (bicyclol, 49.0%), while micrandilactone J (2) was inactive.

General Significance: This is the first comprehensive stereochemical assignment of a non-crystalline schiartane-type nortriterpenoid like 3. This general protocol may contribute towards solving the problems hampering the assignment of the absolute configurations of other members of this class of nortriterpenoids.
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http://dx.doi.org/10.1016/j.bbagen.2017.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053918PMC
December 2017

Marine natural product peptides with therapeutic potential: Chemistry, biosynthesis, and pharmacology.

Biochim Biophys Acta Gen Subj 2018 Jan 24;1862(1):81-196. Epub 2017 Aug 24.

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy and Public Health Sciences, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

The oceans are a uniquely rich source of bioactive metabolites, of which sponges have been shown to be among the most prolific producers of diverse bioactive secondary metabolites with valuable therapeutic potential. Much attention has been focused on marine bioactive peptides due to their novel chemistry and diverse biological properties. As summarized in this review, marine peptides are known to exhibit various biological activities such as antiviral, anti-proliferative, antioxidant, anti-coagulant, anti-hypertensive, anti-cancer, antidiabetic, antiobesity, and calcium-binding activities. This review focuses on the chemistry and biology of peptides isolated from sponges, bacteria, cyanobacteria, fungi, ascidians, and other marine sources. The role of marine invertebrate microbiomes in natural products biosynthesis is discussed in this review along with the biosynthesis of modified peptides from different marine sources. The status of peptides in various phases of clinical trials is presented, as well as the development of modified peptides including optimization of PK and bioavailability.
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http://dx.doi.org/10.1016/j.bbagen.2017.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918664PMC
January 2018

Marine Inspired 2-(5-Halo-1H-indol-3-yl)-N,N-dimethylethanamines as Modulators of Serotonin Receptors: An Example Illustrating the Power of Bromine as Part of the Uniquely Marine Chemical Space.

Mar Drugs 2017 Aug 9;15(8). Epub 2017 Aug 9.

Department of Pharmacognosy, The University of Mississippi, University, MS 38677, USA.

In previous studies, we have isolated several marine indole alkaloids and evaluated them in the forced swim test (FST) and locomotor activity test, revealing their potential as antidepressant and sedative drug leads. Amongst the reported metabolites to display such activities was 5-bromo-,-dimethyltryptamine. Owing to the importance of the judicious introduction of halogens into drug candidates, we synthesized two series built on a 2-(1-indol-3-yl)-,-dimethylethanamine scaffold with different halogen substitutions. The synthesized compounds were evaluated for their in vitro and in vivo antidepressant and sedative activities using the mouse forced swim and locomotor activity tests. Receptor binding studies of these compounds to serotonin (5-HT) receptors were conducted. Amongst the prepared compounds, 2-(1-indol-3-yl)-,-dimethyl-2-oxoacetamide (), 2-(5-bromo-1-indol-3-yl)-,-dimethyl-2-oxoacetamide (), 2-(1-indol-3-yl)-,-dimethylethanamine (), 2-(5-chloro-1-indol-3-yl)-,-dimethylethanamine (), 2-(5-bromo-1-indol-3-yl)-,-dimethylethanamine (), and 2-(5-iodo-1-indol-3-yl)-,-dimethylethanamine () have been shown to possess significant antidepressant-like action, while compounds , , and exhibited potent sedative activity. Compounds , , , and showed nanomolar affinities to serotonin receptors 5-HT and 5-HT₇. The in vitro data indicates that the antidepressant action exerted by these compounds in vivo is mediated, at least in part, via interaction with serotonin receptors. The data presented here shows the valuable role that bromine plays in providing novel chemical space and electrostatic interactions. Bromine is ubiquitous in the marine environment and a common element of marine natural products.
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http://dx.doi.org/10.3390/md15080248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577603PMC
August 2017

Assignment of Absolute Configuration of a New Hepatoprotective Schiartane-Type Nortriterpenoid Using X-Ray Diffraction.

Molecules 2017 Jan 2;22(1). Epub 2017 Jan 2.

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, USA.

A new schiartane-type nortriterpenoid, micrandilactone H was isolated from Finet et Gagnep. Its 2D (two dimension) structure was elucidated by NMR spectroscopic analysis, and it is similar to that of Kadnanolactones H and the absolute configuration was established through X-ray diffraction and ECD data analysis. This represents the first complete assignment of the absolute configuration of a schiartane-type nortriterpenoid by X-ray diffraction and the ECD method. Micrandilactone H showed moderate hepatoprotective activity against -acetyl--aminophenol (APAP)-induced toxicity in HepG2 cells with cell survival rates of 56.84% at 10 μM.
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http://dx.doi.org/10.3390/molecules22010065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155901PMC
January 2017

Antibacterial Activities of Metabolites from (American sycamore) against Fish Pathogenic Bacteria.

J Aquac Res Dev 2015 Oct 15;6(10). Epub 2015 Oct 15.

United States Department of Agriculture, Agricultural Research Service, Natural Products Utilization Research Unit, National Center for Natural Products Research, Post Office Box 1848, Mississippi 38677, USA; Departments of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA; Department of Chemistry of Natural Compounds, National Research Center, Dokki 12622, Cairo, Egypt.

One approach to the management of common fish diseases in aquaculture is the use of antibiotic-laden feed. However, there are public concerns about the use of antibiotics in agriculture and the potential development of antibiotic resistant bacteria. Therefore, the discovery of other environmentally safe natural compounds as alternatives to antibiotics would benefit the aquaculture industries. Four natural compounds, commonly called platanosides, [kaempferol 3---L-(2,3-di---coumaroyl)rhamnoside (), kaempferol 3---L-(2---coumaroyl-3---coumaroyl)rhamnoside (), kaempferol 3---L-(2---coumaroyl-3---coumaroyl)rhamnoside (), and kaempferol 3---L-(2,3-di---coumaroyl)rhamnoside ()] isolated from the leaves of the American sycamore ) tree were evaluated using a rapid bioassay for their antibacterial activities against common fish pathogenic bacteria including , , , and . The four isomers and a mixture of all four isomers were strongly antibacterial against isolates of and . Against ALM-00-173, and showed the strongest antibacterial activities, with 24-h 50% inhibition concentration (IC) values of 2.13 ± 0.11 and 2.62 ± 0.23 mg/L, respectively. Against LA94-426, had the strongest antibacterial activity, with 24-h IC of 1.87 ± 0.23 mg/L. Neither a mixture of the isomers nor any of the individual isomers were antibacterial against isolates of and at the test concentrations used in the study. Several of the isomers appear promising for the potential management of columnaris disease and streptococcosis in fish.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079432PMC
http://dx.doi.org/10.4172/2155-9546.1000364DOI Listing
October 2015

In silico investigation of lavandulyl flavonoids for the development of potent fatty acid synthase-inhibitory prototypes.

Biochim Biophys Acta Gen Subj 2017 Jan 13;1861(1 Pt A):3180-3188. Epub 2016 Aug 13.

College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea. Electronic address:

Background: Inhibition of fatty acid synthase (FAS) is regarded as a sensible therapeutic strategy for the development of optimal anti-cancer agents. Flavonoids exhibit potent anti-neoplastic properties.

Methods: The MeOH extract of Sophora flavescens was subjected to chromatographic analyses such as VLC and HPLC for the purification of active flavonoids. The DP4 chemical-shift analysis protocol was employed to investigate the elusive chirality of the lavandulyl moiety of the purified polyphenols. Induced Fit docking protocols and per-residue analyses were utilized to scrutinize structural prerequisites for hampering FAS activity. The FAS-inhibitory activity of the purified flavonoids was assessed via the incorporation of [H] acetyl-CoA into palmitate.

Results: Six flavonoids, including lavandulyl flavanones, were purified and evaluated for FAS inhibition. The lavandulyl flavanone sophoraflavanone G (2) exhibited the highest potency (IC of 6.7±0.2μM), which was more potent than the positive controls. Extensive molecular docking studies revealed the structural requirements for blocking FAS. Per-residue interaction analysis demonstrated that the lavandulyl functional group in the active flavonoids (1-3 and 5) significantly contributed to increasing their binding affinity towards the target enzyme.

Conclusion: This research suggests a basis for the in silico design of a lavandulyl flavonoid-based architecture showing anti-cancer effects via enhancement of the binding potential to FAS.

General Significance: FAS inhibition by flavonoids and their derivatives may offer significant potential as an approach to lower the risk of various cancer diseases and related fatalities. In silico technologies with available FAS crystal structures may be of significant use in optimizing preliminary leads.
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http://dx.doi.org/10.1016/j.bbagen.2016.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918680PMC
January 2017

SB-224289 Antagonizes the Antifungal Mechanism of the Marine Depsipeptide Papuamide A.

PLoS One 2016 16;11(5):e0154932. Epub 2016 May 16.

Department of Microbiology, University of Tennessee, Knoxville, Tennessee, United States of America.

In order to expand the repertoire of antifungal compounds a novel, high-throughput phenotypic drug screen targeting fungal phosphatidylserine (PS) synthase (Cho1p) was developed based on antagonism of the toxin papuamide A (Pap-A). Pap-A is a cyclic depsipeptide that binds to PS in the membrane of wild-type Candida albicans, and permeabilizes its plasma membrane, ultimately causing cell death. Organisms with a homozygous deletion of the CHO1 gene (cho1ΔΔ) do not produce PS and are able to survive in the presence of Pap-A. Using this phenotype (i.e. resistance to Pap-A) as an indicator of Cho1p inhibition, we screened over 5,600 small molecules for Pap-A resistance and identified SB-224289 as a positive hit. SB-224289, previously reported as a selective human 5-HT1B receptor antagonist, also confers resistance to the similar toxin theopapuamide (TPap-A), but not to other cytotoxic depsipeptides tested. Structurally similar molecules and truncated variants of SB-224289 do not confer resistance to Pap-A, suggesting that the toxin-blocking ability of SB-224289 is very specific. Further biochemical characterization revealed that SB-224289 does not inhibit Cho1p, indicating that Pap-A resistance is conferred by another undetermined mechanism. Although the mode of resistance is unclear, interaction between SB-224289 and Pap-A or TPap-A suggests this screening assay could be adapted for discovering other compounds which could antagonize the effects of other environmentally- or medically-relevant depsipeptide toxins.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154932PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868317PMC
July 2017

New cytotoxic cyclic peroxide acids from sp. marine sponge.

ARKIVOC 2015;2015(5):164-175. Epub 2015 Apr 5.

Department of Chemistry, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia; Department of Chemistry, Faculty of Science, Damietta University, Damietta, Egypt.

Bioassay-guided fractionation of the extract of Jamaican marine sponge sp. followed by preparative TLC and HPLC yielded several known methyl ester cyclic peroxides (), known plakortides (), known bicyclic lactone () and new cyclic peroxide acids (). The chemical structures were elucidated by extensive interpretation of their spectroscopic data. These natural products showed remarkable in vitro cytotoxicity against several cancer cell lines.
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http://dx.doi.org/10.3998/ark.5550190.p008.948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732738PMC
April 2015

Stereochemical Studies of the Karlotoxin Class Using NMR Spectroscopy and DP4 Chemical-Shift Analysis: Insights into their Mechanism of Action.

Angew Chem Int Ed Engl 2015 Dec 16;54(52):15705-10. Epub 2015 Nov 16.

Department of Pharmacognosy, Pharmacology, School of Pharmacy, and Department of Chemistry and Biochemistry, University of Mississippi, University, MS 38677 (USA).

After publication of karlotoxin 2 (KmTx2; 1), the harmful algal bloom dinoflagellate Karlodinium sp. was collected and scrutinized to identify additional biologically active complex polyketides. The structure of 1 was validated and revised at C49 using computational NMR tools including J-based configurational analysis and chemical-shift calculations. The characterization of two new compounds [KmTx8 (2) and KmTx9 (3)] was achieved through overlaid 2D HSQC NMR techniques, while the relative configurations were determined by comparison to 1 and computational chemical-shift calculations. The detailed evaluation of 2 using the NCI-60 cell lines, NMR binding studies, and an assessment of the literature supports a mode of action (MoA) for targeting cancer-cell membranes, especially of cytostatic tumors. This MoA is uniquely different from that of current agents employed in the control of cancers for which 2 shows sensitivity.
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http://dx.doi.org/10.1002/anie.201507418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870721PMC
December 2015

HPLC Plasma Assay of a Novel Anti-MRSA Compound, Kaempferol-3-O-Alpha-L-(2",3"-di-p-coumaroyl)rhamnoside, from Sycamore Leaves.

Nat Prod Commun 2015 Aug;10(8):1383-6

Methicillin-resistant Staphylococcus aureus (MRSA) is a serious pathogen that is resistant to current antibiotic therapy. Thus, there is an urgent need for novel antimicrobial agents that can effectively combat these new strains of drug-resistant "superbugs". Recently, fractionation of an extract from Platanus occidentalis (American sycamore) leaves produced an active kaempferol molecule, 3-O-alpha-L-(2",3"-di-p-coumaroyl)rhamnoside (KCR), in four isomeric forms; all four isomers exhibit potent anti-MRSA activity. In order to further the preclinical development of KCR as a new antibiotic class, we developed and validated a simple analytical method for assaying KCR plasma concentration. Because KCR will be developed as a new drug, although comprising four stereoisomers, the analytical method was devised to assay the total amount of all four isomers. In the present work, both a plasma processing procedure and an HPLC method have been developed and validated. Mouse plasma containing KCR was first treated with ethanol and then centrifuged. The supernatant was dried, suspended in ethanol, centrifuged, and the supernatant was injected into an HPLC system comprising a Waters C18, a mobile phase composing methanol, acetonitrile, and trifluoroacetic acid and monitored at 313 nm. The method was validated by parameters including a good linear correlation, a limit of quantification of 0.27 microg/mL, and high accuracy. In summary, this method allows a rapid analysis of KCR in the plasma samples for pharmacokinetics studies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895204PMC
August 2015

Role of Marine Natural Products in the Genesis of Antiviral Agents.

Chem Rev 2015 Sep 28;115(18):9655-706. Epub 2015 Aug 28.

Department of Pharmacognosy, Pharmacology, Chemistry & Biochemistry, University of Mississippi, School of Pharmacy , University, Mississippi 38677, United States.

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http://dx.doi.org/10.1021/cr4006318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4883660PMC
September 2015

Design, Synthesis and Biological Evaluation of β-Carboline Dimers Based on the Structure of Neokauluamine.

Tetrahedron Lett 2015 Jun;56(23):3515-3517

Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104.

The design, synthesis and biological evaluation (anticancer and antimalarial activity) of bis-β-carbolines, based on the structure of the naturally occurring alkaloid neokauluamine, is described.
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http://dx.doi.org/10.1016/j.tetlet.2015.01.142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527524PMC
June 2015
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