Constraints of Congener Activity

As mentioned in Section 1, molecules as complex as the indole-indoline binary alkaloids warrant an investigation of their critical stereochemistry, including the binary character, with respect to function. The activity profile of the epi C-16, C-14, C-20 -diastereomer of 20 -deoxy VBL is presented in Fig. 5a. The compound inhibits population growth only at micromolar potency, and it lacks detectable antimicrotubule activity. This profile is also typical of the diastereomers of VBL (vincovaline), and of the C-20 congeners examined to date, epideoxy VBL (2), and deoxydesethyl VBL (3). 

The sensitivity of the three types of antimicrotubule activity by VBL to modification at a single site on the cleavamine moiety poses an obvious question Can the cleavamine moiety act alone to exert afunctional attack at this target The answer is no. The 20 -deoxy and epideoxy carbometh- 

In the course of our synthetic efforts, we discovered a new, unnatural conformational isomer of the VBL piperidine ring (see Chapter 2, this volume, for details). This compound is inactive with the microtubule system in vitro and is poorly cytotoxic to cultured tumor cells (Fig. 5b). Therefore, the functional determinism of the C-20 position of VBL-like molecules mediates reactions, as yet unknown, that are dependent on the binary alkaloid structure and on the natural stereochemical configuration at C-16 and C-14 as well as on the conformation of the cleavamine moiety. 

The structure-function relationship of the indole-indoline binary alkaloids was relegated to obscurity until the recent achievement of methodologies for their complete syntheses (see Chapter 2, this volume). Our work with C-20 congeners of VBL has established that the complex interactions between this molecule and tubulin or microtubules can be modified by structural alteration. The various, concentration-dependent reactions of VBL with the microtubule system in vitro are sensitive to subtle modifications at a single molecular locus. In addition, these reactions are distinctive on a mechanistic level as seen from the unique activity profiles of most of our C-20 alkyl congeners. At first light, we can look toward the future with secured optimism. 

Supported by Grants CH-424 and RD-228 from the American Cancer Society and Grant POl CA24543 to the Vermont Regional Cancer Center from the National Cancer Institute. 

---