Publications by authors named "Amir Wahba"

12 Publications

  • Page 1 of 1

Developmental Role of Adenosine Kinase in the Cerebellum.

eNeuro 2021 May-Jun;8(3). Epub 2021 Jun 2.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854

Adenosine acts as a neuromodulator and metabolic regulator of the brain through receptor dependent and independent mechanisms. In the brain, adenosine is tightly controlled through its metabolic enzyme adenosine kinase (ADK), which exists in a cytoplasmic (ADK-S) and nuclear (ADK-L) isoform. We recently discovered that ADK-L contributes to adult hippocampal neurogenesis regulation. Although the cerebellum (CB) is a highly plastic brain area with a delayed developmental trajectory, little is known about the role of ADK. Here, we investigated the developmental profile of ADK expression in C57BL/6 mice CB and assessed its role in developmental and proliferative processes. We found high levels of ADK-L during cerebellar development, which was maintained into adulthood. This pattern contrasts with that of the cerebrum, in which ADK-L expression is gradually downregulated postnatally and largely restricted to astrocytes in adulthood. Supporting a functional role in cell proliferation, we found that the ADK inhibitor 5-iodotubericine (5-ITU) reduced DNA synthesis of granular neuron precursors in a concentration-dependent manner In the developing CB, immunohistochemical studies indicated ADK-L is expressed in immature Purkinje cells and granular neuron precursors, whereas in adulthood, ADK is absent from Purkinje cells, but widely expressed in mature granule neurons and their molecular layer (ML) processes. Furthermore, ADK-L is expressed in developing and mature Bergmann glia in the Purkinje cell layer, and in astrocytes in major cerebellar cortical layers. Together, our data demonstrate an association between neuronal ADK expression and developmental processes of the CB, which supports a functional role of ADK-L in the plasticity of the CB.
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http://dx.doi.org/10.1523/ENEURO.0011-21.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174006PMC
July 2021

Adenosine Kinase Expression Determines DNA Methylation in Cancer Cell Lines.

ACS Pharmacol Transl Sci 2021 Apr 16;4(2):680-686. Epub 2021 Feb 16.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854, United States.

DNA methylation has a major role in cancer, and its inhibitors are used therapeutically. DNA methylation depends on methyl group flux through the transmethylation pathway, which forms adenosine. We hypothesized that an adenosine kinase isoform with nuclear expression (ADK-L) determines global DNA methylation in cancer cells. We quantified ADK-L expression (Western Blot) and global DNA methylation as percent 5-methyldeoxycytidine (5mdC, LC-MS/MS) in three cancer lines (HeLa, HepG2, and U373). ADK-L expression and global DNA methylation correlated positively with the highest levels in HeLa cells compared to U373 and HepG2 cells. To determine whether ADK increases global DNA methylation and to validate its potential therapeutics, we treated HeLa cells with potent ADK inhibitors MRS4203 and MRS4380 (IC 88 and 140 nM, respectively). Both nucleosides, but not a structurally related poor ADK inhibitor, significantly reduced global DNA methylation in HeLa cells in a concentration-dependent manner. Thus, ADK-L is a potential target for the therapeutic manipulation of DNA methylation levels in cancer.
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http://dx.doi.org/10.1021/acsptsci.1c00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033756PMC
April 2021

Ergosterol Peroxide from the Egyptian Red Lingzhi or Reishi Mushroom, Ganoderma resinaceum (Agaricomycetes), Showed Preferred Inhibition of MCF-7 over MDA-MB-231 Breast Cancer Cell Lines.

Int J Med Mushrooms 2020 ;22(4):389-396

Chemistry Department, Faculty of Science, Damietta University, New Damietta City, Egypt; Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA.

Ergosterol peroxide and ganoderic acid AMI were isolated for the first time from the mycelium of the Egyptian Ganoderma resinaceum mushroom. The structure of these two metabolites was established by detailed analysis of 1D and 2D NMR. The isolated compounds were tested for their antitumor in vitro activities in MCF-7 and MDA-MB-231 breast cancer cell lines. Ergosterol peroxide showed preferred inhibition of MCF-7 (ER +ve) cell lines relative to MDA-MB-231 (ER -ve) cell lines with an IC50 of 1.18 μM and 12.82 μM respectively. Our data suggest that ergosterol peroxide targets estrogen receptors.
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http://dx.doi.org/10.1615/IntJMedMushrooms.2020034223DOI Listing
February 2021

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

The molecular basis of cytotoxicity of α-spinasterol from Ganoderma resinaceum: Induction of apoptosis and overexpression of p53 in breast and ovarian cancer cell lines.

J Cell Biochem 2018 05 25;119(5):3892-3902. Epub 2018 Jan 25.

Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, Egypt.

Despite advances in therapy of breast and ovarian cancers, they still remain among the most imperative causes of cancer death in women. The first can be considered one of the most widespread diseases among females, while the latter is more lethal and needs prompt treatment. Thus, the research field can still benefit from discovery of new compounds that can be of potential use in management of these grave illnesses. We hereby aimed to assess the antitumor activity of the phytosterol α-spinasterol isolated from Ganoderma resinaceum mushroom on human breast cancer cell lines (MCF-7, MDA-MB-231), as well as, on human ovarian cancer cell line (SKOV-3). The anti-tumor activity of α-spinasterol, isolated from the mycelial extract of the Egyptian G. resinaceum, on human breast and ovarian cancer cell lines was evaluated by MTT cell viability assay and AnnexinV/propidium iodide apoptosis assay. The molecular mechanism underlying this effect was assessed by the relative expression of the following markers; tumor suppressor (p53, BRCA1, BRCA2), apoptotic marker (Bax) and cell cycle progression markers (cyclin dependent kinases cdk4/6) using real-time PCR. Cell cycle analysis was performed for the three investigated cancer cell lines to explore the effect on cell cycle progression. Our findings showed that α-spinasterol exhibited a higher antitumor activity on MCF-7 cells relative to SKOV-3 cells, while its lowest antitumor activity was against MDA-MB-231 cells. A significant increase in the expression of p53 and Bax was observed in cells treated with α-spinasterol, while cdk4/6 were significantly down-regulated upon exposure to α-spinasterol. Cell cycle analysis of α-spinasterol treated cells showed a G -G arrest. In conclusion, α-spinasterol isolated from G. resinaceum mushroom exerts a potent inhibitory activity on breast and ovarian cancer cell lines in a time- and dose-dependent manner. This can be reasonified in lights of the compound's ability to increase p53 and Bax expressions, and to lower the expression of cdk4/6.
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http://dx.doi.org/10.1002/jcb.26515DOI Listing
May 2018

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

Acantholactone, a new manzamine related alkaloid with an unprecedented δ-lactone and ε-lactam ring system.

Tetrahedron Lett 2012 Nov 7;53(47):6329-6331. Epub 2012 Sep 7.

Department of Pharmacognosy, The School of Pharmacy, The University of Mississippi, University, MS 38677, USA ; Department of Chemistry, Faculty of Science, Damietta University, Egypt.

A new manzamine-related alkaloid with unprecedented δ-lactone and ε-lactam rings called acantholactone (), was isolated from the Indonesian sponge sp. The relative configuration of the two new ring systems was established through detailed analysis of NOESY correlations combined with molecular modeling studies. The absolute configuration of was determined as 12, 24, 25, 26 by comparing the computed electronic circular dichroism (ECD) spectra with experimental values.
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http://dx.doi.org/10.1016/j.tetlet.2012.08.140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601935PMC
November 2012

An α-selective, visible light photocatalytic glycosylation of alcohols with selenoglycosides.

Carbohydr Res 2013 Mar 16;369:42-7. Epub 2013 Jan 16.

Department of Chemistry, Louisiana State University, 232 Choppin Hall, Baton Rouge, LA 70803, United States.

Exceptionally mild procedures for the visible light photocatalytic activation of selenoglycoside donors in the presence of alcohol acceptors have been developed. This process is demonstrated with both 1-phenylselenyl-2,3,4,6-tetra-O-benzyl glucoside (1) and 1-phenylselenyl-2,3,4,6-tetra-O-benzyl galactoside (2). Catalysis is effected with both metal (Ru(bpy)3) and organocatalysts (diphenyldiselenide). Reactions afford, in all cases, primarily the α-anomers with selectivities that vary with solvent. This represents the first example of a visible light-promoted O-glycosylation.
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http://dx.doi.org/10.1016/j.carres.2013.01.004DOI Listing
March 2013

Reductive N-alkylation of nitroarenes: a green approach for the N-alkylation of natural products.

J Org Chem 2012 May 30;77(10):4578-85. Epub 2012 Apr 30.

Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, United States.

A simple, mild, cost-effective, and green approach for the reductive mono-N-alkylation of nitroarenes has been developed. HOAc/Zn are utilized as the reducing system together with a carbonyl compound as an alkyl source in methanol. Excellent yields were obtained with stoichiometric control of mono- over dialkylated products. Application to five complex natural products demonstrated the practical utility of the method.
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http://dx.doi.org/10.1021/jo300303dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4883703PMC
May 2012

New one-pot methodologies for the modification or synthesis of alkaloid scaffolds.

Mar Drugs 2010 Aug 24;8(8):2395-416. Epub 2010 Aug 24.

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

There are several avenues by which promising bioactive natural products can be produced in sufficient quantities to enable lead optimization and medicinal chemistry studies. The total synthesis of natural products is an important, but sometimes difficult, approach and requires the development of innovative synthetic methodologies to simplify the synthesis of complex molecules. Various classes of natural product alkaloids are both common and widely distributed in plants, bacteria, fungi, insects and marine organisms. This mini-review will discuss the scope, mechanistic insights and enantioselectivity aspects of selected examples of recently developed one-pot methods that have been published in 2009 for the synthesis of substituted piperidines, quinolizidines, pyrrolidines, hexahydropyrrolizines, octahydroindolizines and γ-lactams. In addition, progress on the synthesis of β-carboline (manzamine) alkaloids will also be discussed.
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http://dx.doi.org/10.3390/md8082395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953410PMC
August 2010

Structure-activity relationship studies of manzamine A: amidation of positions 6 and 8 of the beta-carboline moiety.

Bioorg Med Chem 2009 Nov 19;17(22):7775-82. Epub 2009 Sep 19.

Department of Pharmacognosy, The School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA.

Twenty manzamine amides were synthesized and evaluated for in vitro antimalarial and antimicrobial activities. The amides of manzamine A (1) showed significantly reduced cytotoxicity against Vero cells, although were less active than 1. The structure-activity analysis showed that linear, short alkyl groups adjacent to the amide carbonyl at position 8 are favored for antimalarial activity, while bulky and cyclic groups at position 6 provided the most active amides. Most of the amides showed potent activity against Mycobacterium intracellulare. The antimicrobial activity profile for position 8 series was similar to that for antimalarial activity profile, in which linear, slightly short alkyl groups adjacent to the amide carbonyl showed improved activity. Two amides 14 and 21, which showed potent antimalarial activity in vitro against Plasmodium falciparum were further evaluated in vivo in Plasmodium berghei infected mice. Oral administration of 14 and 21 at the dose of 30mg/kg (once daily for three days) caused parasitemia suppression of 24% and 62%, respectively, with no apparent toxicity.
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http://dx.doi.org/10.1016/j.bmc.2009.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4883699PMC
November 2009

Semisynthetic latrunculin B analogs: studies of actin docking support a proposed mechanism for latrunculin bioactivity.

Bioorg Med Chem 2009 Nov 16;17(21):7517-22. Epub 2009 Sep 16.

Department of Pharmacognosy, The University of Mississippi, University, MS 38677-1848, United States.

Latrunculins are unique macrolides containing a thiazolidinone moiety. Latrunculins A, B and T and 16-epi-latrunculin B were isolated from the Red Sea sponge Negombata magnifica. N-Alkylated, O-methylated analogs of latrunculin B were synthesized and biological evaluation was performed for antifungal and antiprotozoal activity. The natural latrunculins showed significant bioactivity, while the semisynthetic analogs did not. Docking studies of these analogs into the X-ray crystal structure of G-actin showed that, in comparison with latrunculins A and B, N-alkylated latrunculins did not dock satisfactorily. This suggests that the analogs do not fit well into the active site of G-actin due to steric clashes and provides an explanation for the absence of bioactivity.
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http://dx.doi.org/10.1016/j.bmc.2009.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782694PMC
November 2009
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