The synthesis of the naturally-occurring antitumor agent neplanocin a in optically active form is proposed, as well as the synthesis of certain congeners of neplanocin A. With neplanocin A in hand, examination of its biological properties will be undertaken in order to learn as much as possible about its mechanism of action. The current literature knowledge about the neplanocins, together with the knowledge gained from our own studies, will be used to design congeners of neplanocin a with improved antitumor activity. We are focussing on neplanocin A since it is the most active of the five known neplanocins in vivo (120% increase in life span in L1210 leukemic mice). The synthesis of neplanocin A and all of the proposed congeners will start from D-glucose, utilizing the chirality at C-3 and C-4 of D-glucose for the two hydroxyls in neplanocin A. The nitrogen requisite for building a heterocyclic base will be introduced at C-2 (glucose numbering) by one of several known methods. The ring closure to the cyclopentene ring of neplanocin A will be carried out by an intramolecular Wittig reaction. The overall goal of this research is to develop an antitumor agent, based upon the structure of neplanocin A, which will be of use in treating cancer in man. All synthetic compounds will be tested for cytotoxicity in vitro, and, where warranted, in vivo. Animal testing will begin with the P388 leukemia in mice, and proceed on to other tumors when the activity warrants it. Potentially used compounds will be examined by various biochemical methods in order to learn about their mechanism of action.
| Bennett Jr, L L; Allan, P W; Rose, L M et al. (1986) Differences in the metabolism and metabolic effects of the carbocyclic adenosine analogs, neplanocin A and aristeromycin. Mol Pharmacol 29:383-90 |
