Total synthesis of pladienolide B, initial SAR studies, and the design and synthesis of P1'-P2' macrocyclic HIV-1 protease inhibitors

David Dean Anderson, Purdue University

Abstract

Pladienolide B is a natural product that inhibits human cancer cell proliferation in the low nM range even against drug resistant cell lines. Pladienolide B's antitumor activity is derived from its ability to bind to a spliceosome and inhibit the processing of pre-mRNA to mRNA. As such, it represents a novel chemical scaffold for the development of new cancer drugs against a unique target. We have accomplished an enantioselective synthesis of pladienolide B with the intent of producing chemical analogs in support of SAR studies. Our synthesis features a novel epoxide alkylation strategy along with an efficient asymmetric reduction of a β-keto ester that allows for a highly selective and concise synthesis of the macrocyclic core. We utilized a cross metathesis strategy to synthesize the side chain in order to facilitate the rapid development of analogs. Several analogs were also synthesized and evaluated. This dissertation work also involved the synthesis of a series of P 1'-P2' macrocyclic HIV-1 PIs. Our goal was to introduce a flexible alkyl chain onto darunavir that would constrain its shape to a conformation favorable for binding, create additional hydrophobic interactions within the enzyme's binding site, and retain a certain degree of flexibility to accommodate viral mutations. We selectively introduced a methyl group onto the ring to mimic the isopropyl group of darunavir and began exploring heteroatom substitutions in an effort to form new hydrogen bonds with the protease backbone atoms.

Degree

Ph.D.

Advisors

Ghosh, Purdue University.

Subject Area

Organic chemistry|Medicine

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