This proposal has seven medicinal/biological goals: (1) Synthesize up to seven North 1 and South 1 'slightly simplified' hexacyclic steroidal spiroketal subunits. Convert these materials to South--pyrazine--North trisdecacyclic (thirteen rings) pyrazines using our method for unsymmetrical pyrazine synthesis and compare their anticancer activity to cephalostain 1 (1.2nM avg. NCI panel). (2) Study the contribution of the central arene moiety to anticancer activity by testing pairs of unsymmetrical annulated pyridines derived from the best simplified hexacyclic steroidal subunits. (3) Construct and evaluate one member of a designed new class of inter-phylal agents termed the cephalofurthins to evaluate whether the geranyl geranyl moiety is a recognition element. (4) Prepare and test covalent conjugates of the new agent(s) with folic acid to assay for enhanced (targeted) activity for the treatment of the around 40 percent of cancers which over-express (ten to the 4th power) the folate receptor. (5) Use the biological data from testing of the proposed new materials to complete the mapping of the minimum pharmacophore for the cephalostatin class of antieoplastics. (6) Determine the biological mechanism of action of the trisdecacyclic pyrazines; and (7) Prepare 2-5g of the material which best combines high activity with expedient synthesis to provide a set of new biological tools as well as generating enough agent to initiate clinical trials. Synthesis of the seven hexacyclic spiroketals are projected to require 9-16 operations (compared with 29-31 operations in our 'first generation' synthesis). To accomplish the medicinal/biological goals, efficient new chemistry is required. (A) Utilize a vigorous interactive calculational approach to constantly evaluate synthetic approaches and biological testing data. (B) Test a new siloxysulfonium triflate reagent to effect stereospecific allylic oxidation of a vinyl ether. (C) Investigate the resulting ortho-methylthiophenyldimethylsilyl ether for chemospecific ion-pair self-immolative deprotection. (D) Develop a new annulation of unsymmetrical pyridine rings from 3-ketosteroids via an intramolecular aza-Horner reaction. (E) Generation of the Southern hemispheres requires hydroxylation of the unactivated angular methyl group at the steroidal CD ring junction. This will be accomplished by systematic exploration of the potential of a previously unknown stereospecific dyatropic rearrangement of beta-hydroxyketones and beta-hydroxy lactones to accomplish this transformation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Lees, Robert G
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Purdue University
Schools of Arts and Sciences
West Lafayette
United States
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Ambrose, Andrew J; Santos, Evelyne A; Jimenez, Paula C et al. (2017) Ritterostatin GN 1N , a Cephalostatin-Ritterazine Bis-steroidal Pyrazine Hybrid, Selectively Targets GRP78. Chembiochem 18:506-510
Kanduluru, Ananda Kumar; Banerjee, Prabal; Beutler, John A et al. (2013) A convergent total synthesis of the potent cephalostatin/ritterazine hybrid -25-epi ritterostatin GN1N. J Org Chem 78:9085-92
Kumar, Kanduluru Ananda; La Clair, James J; Fuchs, Philip L (2011) Synthesis and evaluation of a fluorescent ritterazine-cephalostatin hybrid. Org Lett 13:5334-7
Lee, Seongmin; LaCour, Thomas G; Fuchs, Philip L (2009) Chemistry of trisdecacyclic pyrazine antineoplastics: the cephalostatins and ritterazines. Chem Rev 109:2275-314
Lee, Seongmin; Jamieson, Daniel; Fuchs, Philip L (2009) Synthesis of C14,15-dihydro-C22,25-epi north unit of cephalostatin 1 via ""red-ox"" modifications of hecogenin acetate. Org Lett 11:5-8
Lee, Jong Seok; Cao, Hui; Fuchs, Philip L (2007) Ruthenium-catalyzed mild C-H oxyfunctionalization of cyclic steroidal ethers. J Org Chem 72:5820-3
Lee, Jong Seok; Fuchs, Philip L (2005) A biomimetically inspired, efficient synthesis of the South 7 hemisphere of cephalostatin 7. J Am Chem Soc 127:13122-3
Lee, Seongmin; Fuchs, Philip L (2004) An efficient C-H oxidation protocol for alpha-hydroxylation of cyclic steroidal ethers. Org Lett 6:1437-40
Li, Wei; Fuchs, Philip L (2003) Polyphosphoric acid trimethylsilyl ester promoted intramolecular acylation of an olefin by a carboxylic acid: convenient construction of C-18-functionalized delta14-hecogenin acetate. Org Lett 5:4061-4
Lee, Jong Seok; Fuchs, Philip L (2003) New oxidative tools for the functionalization of the cephalostatin north 1 hemisphere. Org Lett 5:2247-50

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