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Author

Lin Lin

Bio: Lin Lin is an academic researcher from University of Illinois at Chicago. The author has contributed to research in topics: Luche reduction & Calanolide A. The author has an hindex of 7, co-authored 12 publications receiving 306 citations.

Papers
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Journal ArticleDOI
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.

182 citations

Journal ArticleDOI
TL;DR: The three chromanone derivatives, (+)-, (-)-, and (+/-)-12-oxocalanolide A (2) are the first reported calanolide analogues capable of inhibiting SIV.

42 citations

Journal ArticleDOI
TL;DR: The synthesis of (+)-calanolide A, an anti-HIV-1 agent, is described, which was resolved by a lipase-catalyzed acylation reaction of compound 2 stereoselectively produced the desired syn diastereomer.
Abstract: 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.

40 citations

Patent
02 Aug 1995
TL;DR: In this paper, a method of preparing (±)-calanolide A, a potent HIV reverse transcriptase inhibitor, from chromene (4) is provided, and useful intermediates for preparing and its derivatives are also provided.
Abstract: 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.

20 citations

Patent
05 Sep 1997
TL;DR: In this paper, a method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided, where the intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (±)-8a.
Abstract: 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.

15 citations


Cited by
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Journal ArticleDOI
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

Journal ArticleDOI
TL;DR: This review concludes that Etherification without Cyclization and N-Alkylation should be considered as separate science, and the proposed treatment of Etherification with Cyclization as a separate science should be reconsidered.
Abstract: 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

909 citations

Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
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