Journal ArticleDOI
Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (±)-calanolide A and its enantiomers
Michael T. Flavin,John D. Rizzo,Albert Khilevich,Alla Kucherenko,Abram Kivovich Sheinkman,Vilayphone Vilaychack,Lin Lin,Wei Chen,Eugenia Mata Greenwood,Thitima Pengsuparp,John M. Pezzuto,Stephen H. Hughes,Thomas M. Flavin,Michael Cibulski,William A. Boulanger,Robert L. Shone,Ze-Qi Xu +16 more
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TLDR
The anti-HIV agent (+/-)-calanolide A (1) has been synthesized in a five-step approach starting with phloroglucinol, which includes Pechmann reaction, Friedel-Crafts acylation, chromenylation with 4,4-dimethoxy- 2-methylbutan-2-ol, cyclization, and Luche reduction.Abstract:
The anti-HIV agent (±)-calanolide A (1) has been synthesized in a five-step approach starting with phloroglucinol [→ 5 → 6 → 11 → 18 → (±)-1], which includes Pechmann reaction, Friedel−Crafts acylation, chromenylation with 4,4-dimethoxy-2-methylbutan-2-ol, cyclization, and Luche reduction. Cyclization of chromene 11 to chromanone 18 was achieved by employing either acetaldehyde diethyl acetal or paraldehyde in the presence of trifluoroacetic acid and pyridine or PPTS. Luche reduction of chromanone 18 at lower temperature preferably yielded (±)-1. Reduction of chromone 12, synthesized by Kostanecki−Robinson reaction from chromene 11, failed to afford (±)-1. The synthetic (±)-1 has been chromatographically resolved into its optically active forms, (+)- and (−)-1. The anti-HIV activities for synthetic (±)-1, as well as resultant (+)- and (−)-1, have been determined. Only (+)-1 accounted for anti-HIV activity, which was similar to the data reported for the natural product, and (−)-1 was inactive.read more
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Natural products to drugs: natural product derived compounds in clinical trials
Mark S. Butler,Mark S. Butler +1 more
TL;DR: Natural product and natural product-derived compounds that are being evaluated in clinical trials or are in registration (as at 31st December 2007) have been reviewed, as well as natural products for which clinical trials have been halted or discontinued since 2005.
Journal ArticleDOI
Natural product drug discovery in the next millennium.
Gordon M. Cragg,David J. Newman +1 more
TL;DR: By use of combinatorial chemical and biosynthetic technology, novel natural product leads will be optimized on the basis of their biological activities to yield effective chemotherapeutic and other bioactive agents.
Journal ArticleDOI
Recent progress in the development of coumarin derivatives as potent anti‐HIV agents
TL;DR: A dicamphanoyl‐khellactone analog, which was discovered and developed in the laboratory, and calanolide A are currently in preclinical studies and clinical trials, respectively.
Journal ArticleDOI
Twenty-Six Years of Anti-HIV Drug Discovery: Where Do We Stand and Where Do We Go?
Youcef Mehellou,Erik De Clercq +1 more
TL;DR: It is apparent that new anti-HIV drugs with acceptable toxicity and resistance profiles and, more importantly, new anti -HIV agents with novel mechanisms of action are clearly needed.
Journal ArticleDOI
Anti-HIV coumarins from calophyllum seed oil
TL;DR: Calophyllum cerasiferum contained (-)-calanolide B as its major coumarin constituent in significant amount and thus constitute a renewable source of this compound.
References
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Journal ArticleDOI
Interactions Between Drug Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase
TL;DR: Genetic characterization of mutant strains of human immunodeficiency virus type 1 has revealed that specific mutations in the RT coding region are responsible for the observed resistance.
Journal ArticleDOI
A semiautomated multiparameter approach for anti-HIV drug screening.
TL;DR: A series of complementary assays for initial follow-up confirmation and prioritization of new active anti-HIV compounds identified by the U.S. National Cancer Institute's large-scale in vitro primary anti-hIV screen yields a maximum amount of antiviral and cytotoxicity information from a minimum amount of sample.
Journal ArticleDOI
Mechanism of inhibition of human immunodeficiency virus type 1 reverse transcriptase and human DNA polymerases alpha, beta, and gamma by the 5'-triphosphates of carbovir, 3'-azido-3'-deoxythymidine, 2',3'-dideoxyguanosine and 3'-deoxythymidine. A novel RNA template for the evaluation of antiretroviral drugs.
William B. Parker,E. L. White,Sue C. Shaddix,Larry J. Ross,Robert W. Buckheit,John A. Secrist,Robert Vince,William M. Shannon +7 more
TL;DR: Assays were developed to assess the mechanism of inhibition by the 5'-triphosphate of carbovir of HIV-1 reverse transcriptase using either RNA or DNA templates that contain all four natural nucleotides, and it is believed that further evaluation of this compound as a potential drug for the treatment of HIV -1 infection is warranted.
Patent
Hiv protease inhibitors
TL;DR: In this paper, the present invention provides a novel dipeptide compound or pharmaceutically acceptable salt thereof which exhibits an excellent HIV protease inhibitory activity and an excellent bioavailability from digestive tracts.
Journal ArticleDOI
Analysis of nonnucleoside drug-resistant variants of human immunodeficiency virus type 1 reverse transcriptase
TL;DR: Analysis of mutants used to analyze calanolide A, 1H,3H-thiazolo[3,4-a]benzimidazole(4i), and the acyclic nucleoside analog 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine suggest that all three drugs interact with HIV-1 RT within the previously defined common binding site for nonnucleoside inhibitors.