Total Synthesis and Evaluation of Vinblastine Analogues Containing Systematic Deep-Seated Modifications in the Vindoline Subunit Ring System: Core Redesign

Abstract

The total synthesis of a systematic series of vinblastine analogues that contain deep-seated structural modifications to the core ring system of the lower vindoline subunit is described. Complementary to the vindoline 6,5 DE ring system, compounds with 5,5, 6,6 and the reversed 5,6 membered DE ring systems were prepared. Both the natural cis and unnatural trans 6,6-membered ring systems proved accessible, with the latter representing a surprisingly effective class for analogue design. Following Fe(III)-promoted coupling with catharanthine and in situ oxidation to provide the corresponding vinblastine analogues, their evaluation provided unanticipated insights into how the structure of the vindoline subunit contributes to activity. Two potent analogues (81 and 44) possessing two different unprecedented modifications to the vindoline subunit core architecture were discovered that matched the potency of the comparison natural products and both lack the 6,7-double bond whose removal in vinblastine leads to a 100-fold drop in activity.

The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry–Biology Interface

“…83,84 Combined with the use of a single-step Fe(III)-promoted coupling of catharanthine with vindoline and a newly developed in situ Fe(III)/NaBH4-promoted hydrogen atom transfer free radical C20′ oxidation, 78,79,85,86 the approach provides vinblastine and its analogs in 8–13 steps. This was used to provide vinblastine analogs not previously accessible by semisynthetic modification of the natural products themselves that contain changes within either the lower vindoline-derived 87–96 or upper catharanthine-derived subunits 97–102 with the late stage divergent 103 introduction of new functionality. In addition to the examination of C10′ substituents, 64 we have prepared more than 400 analogs of vinblastine, defining the role of individual structural features and substituents.…”

Vinblastine 20′ Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance

“…28–30 As a result of these developments, we have prepared several series of key analogs, systematically exploring and defining the impact individual structural features and substituents have on tubulin binding affinity and cancer cell growth inhibition. 10,19 Complementary to the studies detailed herein, we have systematically probed the impact and role of the vindoline C4 acetate, 31,32 C5 ethyl substituent, 33 C6–C7 double bond, 34–36 and the vindoline core structure itself, 36 and have systematically explored the upper catharanthine-derived subunit C20’ ethyl substituent, 37,38 C16’ methyl ester, 39 and added C10’ or C12’ indole substitutions. 40 In addition and in preceding studies, we have shown that replacement of the C20'-OH with 20’ ureas was possible, 41 that substantial 42 and even remarkable 43 potency enhancements were obtainable with such 20’ ureas, and that some exhibited further improvements in activity against vinblastine-resistant cancer cell lines.…”

Tandem Intramolecular Diels–Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Initial Scope and Applications

“…64 The 5,5-vindoline subunit analogue was accessed through an intermediate previously enlisted in the asymmetric synthesis of vindoline, 56 where a remarkably facile thermal deformylation reaction of 10 generated 11 directly (50%). 64 Presumably this unusual reaction occurs by reversible iminium ion formation followed by loss of formaldehyde to generate a stabilized singlet carbene that undergoes an insertion of the proximal C3 alcohol for reclosure of the N,O -ketal, affording the 5,5-D,E ring analogue of vindoline (Figure 11b). Increasing the length of the dipolarophile tether by one carbon and varying the length of the dienophile tether provided cycloadducts bearing the corresponding 6,5- and 6,6-DE ring system analogues.…”

“…Most interesting in this probe was that it was the analogues that bore the greatest departure from the natural products ( 12 and 13 ) that exhibited the best activity, matching that of the comparison natural products. 64 Unlike modifications to peripheral substituents, such core redesign is rarely explored in complex natural products, and was possible only because of the power of the oxadiazole cycloaddition cascade.…”