| A series of N-acyl O-amino derivatives of seco-CBI-indole2 were examined as prototypical members of a unique class of reductively activated prodrugs of the duocarmycin and CC-1065 family of antitumor agents. These prodrugs were designed to be preferentially activated in hypoxic tumor environments, which carry an intrinsically higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives by nucleophilic cleavage of a weak N--O bond. A remarkable range of stabilities and a resulting direct correlation with in vitro/in vivo biological potencies was observed for these prodrugs. An in vivo evaluation of several of the prodrugs demonstrated that some approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), suggesting the prodrugs may offer an additional advantage related to a controlled or targeted release.;A short, asymmetric synthesis of CBI was described. Treatment of the iodo-epoxide with MeMgBr, EtMgBr, or i-PrMgBr at room temperature directly provided an optically pure alcohol product in 82--87% yield (99% ee) which was easily elaborated to CBI. Overall, this approach represents the most efficient (9-steps, 31% overall) and effective (99% ee) route to the optically pure CBI alkylation subunit yet described.;Divergent total syntheses of (--)-aspidospermine and (+)-spegazzinine and their extensions to the synthesis of C19-epi-aspidospermine and C3-epi-spegazzinine were detailed, confirming the relative stereochemistry and establishing the absolute configuration of (+)-spegazzinine. A powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole provided the pentacyclic skeleton and all the requisite stereochemistry of the natural products in a single reaction that forms three rings, four C--C bonds, and five stereocenters.;The synthesis and characterization of CbBI containing a ring expanded fused cyclobutane (vs cyclopropane) was detailed. The approach to the preparation of CbBI relied on a previously unknown Ar-4' spirocyclization of a phenol onto a tethered alkyl. The characterization of the CbBI-based agents revealed their exceptional stability and exquisite reaction regioselectivity. In addition, the in vitro cytotoxic activities of the CbBI-based agents were found to follow a well-established parabolic relationship where compounds with very low chemical reactivity exhibit less potent activity. |
