Robert L. Shone

Bio: Robert L. Shone is an academic researcher from University of Illinois at Chicago. The author has contributed to research in topics: Calanolide A & Luche reduction. The author has an hindex of 3, co-authored 4 publications receiving 213 citations.

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

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.

Synthesis, Chromatographic Resolution, and Anti‐Human Immunodeficiency Virus Activity of (.+‐.)‐Calanolide A and Its Enantiomers.

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.

Novel Approach for Synthesis of (.+‐.)‐Calanolide A and Its Anti‐HIV Activity.

Abstract: Anti-HIV agent (±)-calanolide A ( 1 ) has been synthesized. The key intermediate, chromene 5 , was synthesized by the sequence of Pechmann reaction, acylation and chromenylation by 4,4-dimethoxy-2-methylbutan-2-ol. The anti-HIV activity for synthetic (±)- 1 has been determined and compared with the natural product.

Natural product drug discovery in the next millennium.

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.

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

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.

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

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.