Steroidal anticancer agents
Abstract
This thesis describes the design, synthesis, and bioactivity of steroidal anticancer agents. The program aimed to discover new chemistry, provide concise routes to natural and analogue cytotoxins, and comprehend their structure-activity relationships. The work resulted in advances in nine related projects: (1) asymmetric synthesis of bissteroidal pyrazines, including the first syntheses of the currently most potent natural (cephalostatin 1) and designed hybrid (ritterostatin GN1N) examples; (2) new chemistry for ring-opening and functionalization of spiroketals; (3) design and synthesis of solasodine and OSW monosteroid analogues; (4) new C/D ring chemistry illuminating subunit biosynthesis and nucleophilicity in bioactivity; (5) proximal functionalization topics and design of a unified approach to all subunits, including stereochemical and heteroatom analogues; (6) rational expansion of the SAR via new analogues, new testing measures, and extension to ritterazines; (7) review of all known mono and bissteroidal antineoplastics, definition of their common minimum pharmacophore, and discovery that both classes are apoptoxins; (8) development and validation by experiment of computational methods that accurately predict spiroketal-derived oxacarbenium ion mediated chemistry; (9) discovery of a precise correlation between the calculated energy cost to access oxacarbenium ions, proposed as active intermediates, and the in vitro cytotoxicity of steroidal anticancer agents, thereby predicting structure or bioactivity from whichever of the two is known.
Degree
Ph.D.
Advisors
Fuchs, Purdue University.
Subject Area
Organic chemistry|Biochemistry|Oncology
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