Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (±)-calanolide A and its enantiomers
15 Mar 1996-Journal of Medicinal Chemistry (American Chemical Society)-Vol. 39, Iss: 6, pp 1303-1313
TL;DR: 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.
Citations
More filters
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.
976 citations
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.
Abstract: Nature has been a source of medicinal agents for thousands of years, and an impressive number of modern drugs have been isolated from natural sources, many based on their use in traditional medicine. In the past century, however, an increasing role has been played by microorganisms in the production of antibiotics and other drugs for the treatment of some serious diseases. Advances in the description of the human genome, as well as the genomes of pathogenic microbes and parasites, is permitting the determination of the structures of many proteins associated with disease processes. With the development of new molecular targets based on these proteins, there is an increasing demand for novel molecular diversity for screening. Natural products will play a crucial role in meeting this demand through the continued investigation of world's biodiversity, much of which remains unexplored. With less than 1% of the microbial world currently known, advances in procedures for microbial cultivation and the extraction of nucleic acids from environmental samples from soil and marine habitats, will provide access to a vast untapped reservoir of genetic and metabolic diversity. The same holds true for nucleic acids isolated from symbiotic and endophytic microbes associated with terrestrial and marine macroorganisms. 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. The investigation of these resources requires multi-disciplinary, national, and international collaboration in the discovery and development process.
452 citations
Cites methods from "Synthesis, chromatographic resoluti..."
...Medichem Research had developed a synthesis of (+)-calanolide A (Flavin et al., 1996) under a Small Business Innovation Research (SBIR) grant from the NCI....
[...]
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.
Abstract: Numerous plant-derived compounds have been evaluated for inhibitory effects against HIV replication, and some coumarins have been found to inhibit different stages in the HIV replication cycle. This review article describes recent progress in the discovery, structure modification, and structure-activity relationship studies of potent anti-HIV coumarin derivatives. A dicamphanoyl-khellactone (DCK) analog, which was discovered and developed in our laboratory, and calanolide A are currently in preclinical studies and clinical trials, respectively.
438 citations
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.
Abstract: The human immunodeficiency virus (HIV) has now been established as the causative agent of the acquired immunodeficiency syndrome (AIDS) for over 20 years. During this time an unprecedented success has been achieved in discovering anti-HIV drugs as reflected by the fact that there are now more drugs approved for the treatment of HIV than for all other viral infections taken together. The currently Food and DrugAdministration (FDA) approved anti-HIVdrugs can be divided into seven groups: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). This arsenal of drugs, which is used in combinations, has moved the prognosis of HIV patients from that of high morbidity and mortality to, for many at least, a chronic, manageable but still complex disease. However, the use of these drugs has been relatively limited by their toxicity, drug resistance development, and more worryingly, the fact that some newly HIV-infected patients carry viruses that are already resistant to the currently approvedAIDS treatments. These issues along with drug-related side effects as well as, in some cases, poor tolerability of these drugs make it 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.
366 citations
TL;DR: Calophyllum cerasiferum contained (-)-calanolide B as its major coumarin constituent in significant amount and thus constitute a renewable source of this compound.
281 citations
References
More filters
TL;DR: A 3.5 angstrom resolution electron density map of the HIV-1 reverse transcriptase heterodimer complexed with nevirapine, a drug with potential for treatment of AIDS, reveals an asymmetric dimer.
Abstract: A 3.5 angstrom resolution electron density map of the HIV-1 reverse transcriptase heterodimer complexed with nevirapine, a drug with potential for treatment of AIDS, reveals an asymmetric dimer. The polymerase (pol) domain of the 66-kilodalton subunit has a large cleft analogous to that of the Klenow fragment of Escherichia coli DNA polymerase I. However, the 51-kilodalton subunit of identical sequence has no such cleft because the four subdomains of the pol domain occupy completely different relative positions. Two of the four pol subdomains appear to be structurally related to subdomains of the Klenow fragment, including one containing the catalytic site. The subdomain that appears likely to bind the template strand at the pol active site has a different structure in the two polymerases. Duplex A-form RNA-DNA hybrid can be model-built into the cleft that runs between the ribonuclease H and pol active sites. Nevirapine is almost completely buried in a pocket near but not overlapping with the pol active site. Residues whose mutation results in drug resistance have been approximately located.
1,902 citations
TL;DR: It would be premature to alter any treatment protocols for HIV-infected individuals at present, as it cannot be determined from this small sample of patients whether development of a less sensitive virus phenotype results in clinical resistance.
Abstract: The drug sensitivities of human immunodeficiency virus (HIV) isolates from a group of patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) who were receiving zidovudine (3'-azido-3'-deoythymidine, AZT) therapy were tested by means of a newly developed plaque assay in CD4+ HeLa cells. Fifty percent inhibitory dose (ID50) values of 18 isolates from untreated individuals ranged between 0.01 microM and 0.05 microM. In contrast, most isolates from patients who had received zidovudine for 6 months or more exhibited decreased sensitivity characterized by changes in ID50 or ID95 values (or both), with isolates from several patients (5/15) showing 100-fold increases in ID50. The latter isolates were also insensitive to 3'-azido-2',3'-dideoxyuridine; however, the isolates were still sensitive to 2',3'-dideoxycytidine, 2',3'-dideoxy-2',3'-didehydrothymidine, or phosphonoformate. It cannot be determined from this small sample of patients whether development of a less sensitive virus phenotype results in clinical resistance. Appearance of such variants was not associated with a consistent increase in viral p24 concentrations in patient plasma and did not herald any sudden deterioration in clinical status. More extensive studies are required to determine the clinical significance. Thus, it would be premature to alter any treatment protocols for HIV-infected individuals at present.
1,562 citations
TL;DR: In the future, non-nucleoside-type drugs will likely become more important in the experimental therapy of AIDS, and antiretroviral therapy will exert major effects against the morbidity and mortality caused by HIV.
Abstract: The development of antiretroviral therapy against acquired immunodeficiency syndrome (AIDS) has been an intense research effort since the discovery of the causative agent, human immunodeficiency virus (HIV). A large array of drugs and biologic substances can inhibit HIV replication in vitro. Nucleoside analogs--particularly those belonging to the dideoxynucleoside family--can inhibit reverse transcriptase after anabolic phosphorylation. 3'-Azido-2',3'-dideoxythymidine (AZT) was the first such drug tested in individuals with AIDS, and considerable knowledge of structure-activity relations has emerged for this class of drugs. However, virtually every step in the replication of HIV could serve as a target for a new therapeutic intervention. In the future, non-nucleoside-type drugs will likely become more important in the experimental therapy of AIDS, and antiretroviral therapy will exert major effects against the morbidity and mortality caused by HIV.
767 citations
TL;DR: In this paper, an effective and optimally safe microculture method for rapid and convenient assay of the in vitro cytopathic effects of human immunodeficiency virus (HIV-1) on human lymphoblastoid or other suitable host cells.
Abstract: We have developed an effective and optimally safe microculture method for rapid and convenient assay of the in vitro cytopathic effects of human immunodeficiency virus (HIV-1) on human lymphoblastoid or other suitable host cells. The assay procedure is applicable to the evaluation of drug effects on in vitro infections induced directly in cultured host cells by cell-free HIV-1 or by coculture with H9 cells chronically infected with HIV-1. The assay uses a newly developed tetrazolium reagent that is metabolically reduced by viable cells to yield a soluble, colored formazan product measurable by conventional colorimetric techniques. This simple microassay minimizes the number of plate manipulations typically required with other assay methods and, coupled with computerized data collection and analysis, facilitates large-scale screening of agents for potential antiviral activity. To support and enhance the discovery of new anti-HIV-1 agents, the National Cancer Institute is offering investigators worldwide the opportunity to submit new candidate agents for anti-HIV-1 screening with this method.
725 citations