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 ..

An enantioselective and convergent total synthesis of pladienolide B (1) is described
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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 (41ad) of pladienolide B.

Our novel synthetic strategy enables the rapid synthesis of other new analogs of pladienolide in order to develop selective anticancer lead compounds.
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TOTAL SYNTHESIS OF PLADIENOLIDE B AND PLADIENOLIDE D

In 2004, Sakai et al. reported the isolation and structural characterization of seven novel 12-membered macrocyclic compounds named pladienolide A-G from a culture of an engineered strain of Streptomyces platensis, Mer-11107. Initial screening studies showed these compounds were capable of inhibiting the proliferation of human cancer cells with low nanomolar IC50 values. Interestingly, pladienolides maintained this activity against multiple drug resistant cancer cells. Furthermore, they exhibited a novel mechanism of action by binding to the SF3b subunit of the spliceosome, inhibiting the splicing of pre-mRNA to translatable mRNA. The unspliced pre-mRNA is exported from the nucleus to the cytoplasm resulting in inhibition of cell growth. To date, the pladienolides and the structurally distinct FR901464 are the only known molecular scaffolds capable of modulating splicing and generating an antitumor response. Consequently, these compounds have shown tremendous potential to become a new class of anticancer agents. In 2008, clinical trials were initiated using E7107, a pladienolide D analog, for the treatment of various cancers. Not surprisingly, the chemistry and biology of the pladienolides attracted immense attention. To date, Kotake and co-workers reported the first total synthesis of the most active compounds, pladienolide B and D. Skaanderup et al. published a synthetic pathway to the macrocyclic core of the enantiomer of pladienolide B, while Burkart and co-workers have reported their efforts on constructing and modifying the side chain. Recently, both Maier and Webb have reported progress in the development of pladienolide based analogs albeit with reduced biological activity. Our interest in pladienolide B arose from its novel mechanism of action and its unique structural features. We sought to develop a convergent route to pladienolide B that could facilitate subsequent structure activity relationship studies and synthesis of structural variants. Herein, we report a concise, enantioselective synthesis of pladienolide B.

Synthesis of the macrocyclic core of (-)-pladienolide B

We have also been engaged in a successful effort to design new effective and highly active synthetic analogs of FR901464 and 2 by the application of a consensus pharmacophore hypothesis. We believed that we could extend our approach by the generation of a new structurally simplified scaffold based on herboxidiene. Thus, using the guidance of our pharmacophore hypothesis, we designed a hybrid molecule (3) from herboxidiene (1) and pladienolide B (2), (). This hybrid 3 has the tetrahydropyran core of 1 (red) and side chain of 2 (blue). Based on our pharmacophore model we anticipated that compound 3 could incorporate the correct molecular geometry as well as all of the key SF3B1 interaction features.

The seven pladienolide derivatives discovered all ..

In summary, we have accomplished an enantioselective synthesis of pladienolide B. The synthetic route is convergent and readily scaleable. Overall, our synthesis involved 31 total steps from commercially available material. The longest linear path was 16 steps with an overall yield of 1.4%. This represents a significant improvement over Kotake’s route which required 59 total steps (22 longest linear) from commercially available material. The syntheses featured an effective aymmetric reduction of a β-keto ester, a cross metathesis reaction and Julia-Kocienski olefinations. Other key reactions included a Sharpless asymmetric epoxidation and Brown asymmetric crotylboration reactions. The synthesis will provide convenient access to a variety of derivatives. Further investigations of structural and biological studies are in progress.