A synthetic entry to pladienolide B and FD-895 - ScienceDirect
The total synthesis of various biologically important natural products is an important part of my group?s research. Our underlying interests include the development of new synthetic methodologies as well as the opportunity to establish important structure-function relationships for these rare natural products with medicinal significance. We have synthesized a variety of complex natural products with significant medicinal potential. These Bioactive molecules are shown below. We achieved the first synthesis of laulimalide, a sponge-derived macrolide that has been isolated in only miniscule quantities. Our chemical synthesis of laulimalide enabled us to carry out further biological studies in collaboration with Dr. Ernie Hamel at the National Cancer Institute. While laulimalide was thought to resemble paclitaxel in its effects on cellular microtubules, our studies established that laulimalide stabilizes microtubules by binding at a novel site on the tubulin dimer. Laulimalide appears to be the first example that binds to different drug-binding site on tubulin. Laulimalide was able to enhance tubulin assembly synergistically with paclitaxel. We have shown that the epoxide functionality is not essential for activity as our synthetic desoxylaulimalide has shown similar potency as laulimalide. We have also demonstrated that peloruside A, Peloruside B, and zampanolide are novel microtubule stabilizing agents. We have carried out efficient laboratory syntheses of these important anticancer natural products and we investigated in-depth biology of various structural variants. Furthermore, we have carried out enantioselective synthesis of doliculide and using synthetic doliculide we established its biological mechanism of action.
Over the years, my research group has completed the synthesis of many other biologically important natural products including: anticancer agents such as Amphidinolide T, Amphidinolide W, Spongidepsin, Cryptophysin B, Cryptophysin 52, and Doliculide, MDR- inhibitor Hapalosin, streptogramin antibiotic Madumycin, pancreatic lipase inhibitor, tetrahydrolipstatin, antimalarial agent boronolide, gastroprotective agent, AI-77-B, reverse transcriptase inhibitor, taurospongin, nucloside antibiotic sinefungin, polyoxin-J, peloruside A, largazole, platensimycins and herboxadine. We have also completed the synthesis of (-)-lasonolide A. In collaboration with Dr. Yves Pommier at the NCI, we recently showed that lasonolide possesses a novel chromosome condensing ability. Using synthetic lasonolide and its structural variants, we have investigated their biological mechanism of action. Recently, we have completed enantioselective synthesis of antifungal natural products, vividofungin, and antitumor natural products, herboxidiene, pladienolide, spliceostatins, and FP901464 which are very potent inhibitors of spliceosome. Our work on pladienolide, herboxidiene, and spliceostatins allowed the establishment of structure-activity studies and design of less complex inhibitors for cancer chemotherapy.
Total Synthesis of the Potent Antitumor Macrolides Pladienolide B ..
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Synthesis of Pladienolide B and Its 7-Epimer with …
An enantioselective and convergent total synthesis of pladienolide B (1) is described. Pladienolide B binds to the SF3b complex of a spliceosome and inhibits mRNA splicing activity. The synthesis features an epoxide opening reaction, an asymmetric reduction of a β-keto ester, and a cross metathesis strategy for the side chain synthesis.
Patent EP1935893A1 - Total synthesis of pladienolide b …
An enantioselective synthesis of natural anticancer macrolide pladienolide B is described. The synthetic highlights include Sharpless asymmetric epoxidation, ring closing metathesis (RCM), Ireland–Claisen rearrangement, Shi epoxidation, and Pd-catalyzed Stille coupling as key steps. The synthetic route also allowed the synthesis of the truncated analogues (41a–d) of pladienolide B.
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