This proposal weaves together three themes with a view toward producing modalities of value in regards to cancer. The first is that synthetic organic chemistry has made major advances, such as to render it a usable resource in the discovery of new modalities in medicine. The second theme is that a class of structurally diverse, biologically active molecules, in most cases with respect to cancer targets, known as SMNPs (small molecule natural products), have a remarkable record in producing new drugs. This may take the form of SMNPs themselves, chemical derivatives of SMNPs, or synthetic intermediates derived through the process of molecular editing. The third notion is that synthesis has reached the stage where biologicals, including oligosaccharides and glycopeptides of high complexity and value, can be assembled in the laboratory. The proposal is divided into 11 programs. Eight use SMNPs as springboard for new discoveries in therapy. Three others are focused on synthetic biologicals which are directed to immune system targets - one against HIV and two against prostate cancer, either via improved prospects for diagnosis or as a means of creating a prostate cancer-directed vaccine. The SMNP-based programs center around: (1) Migrastatin, which finds potentially critical application against tumor metastasis. We have found, through a sequence of synthesis, diverted total synthesis, and molecular editing, a series of simplified migrastatins that virtually block colonization of primary tumors to other target organs; (2) Maoecrystal, a complex terpenoid-like structure which is about 50 times more potent against certain cancer cell lines than cis-platin; (3) Cortistatin, a potent anti-angiogenesis agent of complex molecular architecture; (4) Platensimycin, a gram-positive antibacterial, whose target is cell wall biosynthesis; (5) Aplykurodinone, a stereochemically challenging terpene-like structure, and a member of a family of cytotoxic agents; (6) Hyperforin, a complex polyprenyloid which induces apoptosis in cancer cells; (7) Actinophyllic Acid, an alkaloidal submicromolar inhibitor of carboxypeptidases; and (8) Piperazimycin, a complex depsipeptide, containing two difficultly installable piperazic acids, which is active against a panel of cancer cell lines at 100 nM. In addition, three programs will be directed to the synthesis of biological level molecules. Program 9 contemplates an anti-HIV vaccine based on the carbohydrate sector of the gp120 antigen. Program 10 involves assembling a PSA-based construct using the very complex carbohydrate domain to differentiate between highly aggressive and less aggressive prostate cancers, thereby providing additional calibration of conventional PSA readings. Program 11 entails the synthesis and evaluation of a complex vaccine against prostate cancer, based on the membrane-localized PSMA. In summary, we foresee a program which integrates chemistry, cell biology, immunology, and development for chemical evaluation with a view to advancing synthesis and medicine.
The proposal brings to bear the resources of target directed organic synthesis to create complex molecular entities with opportunities for translation to medicine, particularly in the context of cancer and HIV. ? ? ?
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