Publications by authors named "Guna Sakaine"

3 Publications

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Isolation, chemistry, and biology of pyrrolo[1,4]benzodiazepine natural products.

Med Res Rev 2021 Apr 13. Epub 2021 Apr 13.

Latvian Institute of Organic Synthesis, Riga, Latvia.

The isolation of the antitumor antibiotic anthramycin in the 1960s prompted extensive research into pyrrolo[1,4]benzodiazepines (PBD) as potential therapeutics for the treatment of cancers. Since then, nearly 60 PBD natural products have been isolated and evaluated with regard to their biological activity. Synthetic studies and total syntheses have enabled access to PBD analogues, culminating in the development of highly potent anticancer agents. This review provides a summary of the occurrence and biological activity of PBD natural products and covers the strategies employed for their total syntheses.
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http://dx.doi.org/10.1002/med.21803DOI Listing
April 2021

Lead Optimization of Phthalazinone Phosphodiesterase Inhibitors as Novel Antitrypanosomal Compounds.

J Med Chem 2020 04 26;63(7):3485-3507. Epub 2020 Mar 26.

Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.

Human African trypanosomiasis is causing thousands of deaths every year in the rural areas of Africa. In this manuscript we describe the optimization of a family of phtalazinone derivatives. Phosphodiesterases have emerged as attractive molecular targets for a novel treatment for a variety of neglected parasitic diseases. Compound resulted in being a potent TbrPDEB1 inhibitor with interesting activity against in a phenotypic screen. Derivative was studied in an acute mouse disease model but unfortunately showed no efficacy due to low metabolic stability. We report structural modifications to achieve compounds with an improved metabolic stability while maintaining high potency against TbrPDEB1 and . Compound presented a good microsomal stability in mouse and human microsomes and provides a good starting point for future efforts.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00985DOI Listing
April 2020

Modified Julia-Kocienski Reagents for a Stereoselective Introduction of Trisubstituted Double Bonds: A Formal Total Synthesis of Limazepine E and Barmumycin.

J Org Chem 2018 05 18;83(9):5323-5330. Epub 2018 Apr 18.

Latvian Institute of Organic Synthesis , Aizkraukles 21 , Riga LV-1006 , Latvia.

A formal total synthesis of pyrrolo[1,4]benzodiazepine anticancer antibiotic family member limazepine E is described. The synthesis features a stereoselective introduction of a trisubstituted double bond using novel sterically demanding Julia-Kocienski reagents, allowing the number of linear steps to be significantly reduced. The potential of the newly developed reagents has also been demonstrated by the formal total synthesis of barmumycin.
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http://dx.doi.org/10.1021/acs.joc.8b00643DOI Listing
May 2018