A collaboration has been established between the synthesis group of Philip. L. Fuchs (Purdue) and three biological/biochemical groups including Philip. A. Low (Purdue); Peng Huang (M. D. Anderson Cancer Center); and John Beutler (NIH-Bethesda). The goals involve synthesis and testing of about four new mechanism and calculation based analogs of the hyper-potent cephalostatin-1; and to define, compare, and contrast the mechanism of action with structurally and biologically similar compounds: the steroidal glycosides OSW-1 and Solamargene. ? ? While new agents are being prepared and evaluated, the collaborators will continue testing the now available, synthetic analog, 23'deoxy-cephalostatin 1 (23'DCST-1). Proposed testing will involve preparing folate-linked dipeptide esters of 23'DCST-1, evaluating a proposed self-immolative cleavage to the free cephalostatin drug after receptor-mediated endocytosis, and characterizing the folate-cephalostatin drugs in vitro and in vivo. A second front will feature mechanistic studies to determine the anticancer activity and selectivity of 23'DCST-1 and other cephalostatin analogs in vitro, elaborating the newly-determined mitochondrial-based mechanism of action using TEM to probe the mitochondria ultrastructure, probing the mitochondria function with respect to the apoptotic end point, and testing cephalostatin analogs as potential inhibitors of the mitochondria! respiration chain. Therapeutic activity of lead compounds will then be compared in animal models. Continued testing of all new analogs using the NCI 60 cell panel will be combined with using new affinity probes including 23'DCST-1-glycine-biotin to determine which proteins, if any, undergo formation of covalent bonds to this class of drugs. The PI's group will prepare and maintain a web-based information site on the chemistry/biology/pharmacology/ medicine of the cephalostatin analogs, actively recruit new collaborators, and supply interested scientists with synthetic material for testing. The overall goal of this program is to ultimately provide one or more collaborators with multi-gram quantities of the best agent(s) in order to proceed to Phase I human trials. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01CA060548-13
Application #
6927494
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
1996-08-09
Project End
2010-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
13
Fiscal Year
2005
Total Cost
$318,622
Indirect Cost
Name
Purdue University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
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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