Natural products to drugs: natural product derived compounds in clinical trials

10. Patented Literature 2616 10.1. Esterification 2616 10.2. Ether Formation 2619 10.2.1. Etherification without Cyclization 2619 10.2.2. Etherification with Cyclization 2624 10.3. N-Alkylation 2625 10.4. Other Reactions 2627 11. Summary and Outlook 2628 12. Note Added in Proof 2628 13. Abbreviations Used in This Review 2629 14. Acknowledgments 2629 15. Supporting Information Available 2630 16. References 2630

Mitsunobu and Related Reactions: Advances and Applications

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.

Natural product drug discovery in the next millennium.

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.

Recent progress in the development of coumarin derivatives as potent anti‐HIV agents

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.

Twenty-Six Years of Anti-HIV Drug Discovery: Where Do We Stand and Where Do We Go?

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.

Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (±)-calanolide A and its enantiomers

In vitro anti-human immunodeficiency virus (HIV) activity of the chromanone derivative, 12-oxocalanolide A, a novel NNRTI

The synthesis of (+)-calanolide A ( 1 ), an anti-HIV-1 agent, is described. A TiCl 4 -mediated aldol reaction of compound 2 stereoselectively produced the desired syn diastereomer (±)- 5 , which was resolved by a lipase-catalyzed acylation reaction. Under Mitsunobu conditions (Ph 3 P/DEAD), the syn aldol product (+)- 5 led to the formation of trans -2,3-dimethyl chroman-4-one [(+)- 3 ] with 94% ee , while the anti aldol product (+)- 6 yielded both trans and cis derivatives (+)- 3 and (+)- 4 with 60% and 68% ee , respectively. Luche reduction on (+)- 3 led to (+)- 1 and (+)-calanolide B in a ratio of 9:1.

Synthesis of (+)-calanolide A, an anti-HIV agent, Via enzyme-catalyzed resolution of the aldol products

A method of preparing (±)-calanolide A, (1), a potent HIV reverse transcriptase inhibitor, from chromene (4) is provided. Useful intermediates for preparing (±)-calanolide A and its derivatives are also provided. According to the disclosed method, chromene (4) intermediate was reacted with acetaldehyde diethyl acetal or paraldehyde in the presence of an acid catalyst with heating, or a two-step reaction including an aldol reaction with acetaldehyde and cyclization either under acidic conditions or neutral Mitsunobu conditions, to produce chromanone (7). Reduction of chromamone (7) with sodium borohydride, in the presence of cerium trichloride, produced (±)-calanolide A. A method for resolving (±)-calanolide A into its optically active forms by a chiral HPLC system or by enzymatic acylation and hydrolysis is also disclosed. Finally, a method for treating or preventing viral infections using (±)-calanolide or (-)-calanolide is provided.

Method for the preparation of (+)-calanolide A and intermediates thereof

A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (±)-8a. Separation and enzyme-mediated resolution of (±)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.

Lin Lin

Papers

Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (±)-calanolide A and its enantiomers

In vitro anti-human immunodeficiency virus (HIV) activity of the chromanone derivative, 12-oxocalanolide A, a novel NNRTI

Synthesis of (+)-calanolide A, an anti-HIV agent, Via enzyme-catalyzed resolution of the aldol products

Method for the preparation of (+)-calanolide A and intermediates thereof

Method for the preparation of (+)-calanolide a and analogues thereof