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

Abstract

A series of 180 vinblastine 20’ amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure–activity relationships and a structural model were developed in the studies which provided many such 20’ amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogs that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux.

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

“…Several 20′ amides were discovered that match or exceed the potency of vinblastine, but that are not subject to Pgp efflux and its derived vinblastine resistance. 102 Within this series and reflecting an additional impact of a single heavy atom change, a benzamide substituent X was found to predictably impact activity, displaying a fundamental linear relationship between potency (−log IC 50 , HCT116) and the electronic character of the aryl substituent (σ p ) (Figure 7). All benzamides shown in Figure 7 are more potent than vinblastine and those that bear an aryl electron-donating substituent, some of which constitute single heavy atom additions, improve the H-bond acceptor ability of the added amide carbonyl that in turn proportionally increase the measured tubulin binding affinity (not shown) and functional activity (Figure 7).…”

“…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.…”

Perplexing Role of P-Glycoprotein in Tumor Microenvironment

“…Similarly, an isoindoline urea derivative of vinblastine (at the same chemical position C20) was shown to possess 100 fold higher cytotoxic potential against vinblastine-resistant cancer cell lines (84,85). Along the lines, an aryl amide derivatives of vinblastine has also been demonstrated to be less sensitive to P-gp mediated efflux in cancer cell lines (86). However, the therapeutic efficiency of these drugs is yet be prove in clinical settings.…”

Harnessing the Chemistry of the Indole Heterocycle to Drive Discoveries in Biology and Medicine

“…[56,58] The Bogerl ab hasm ade significant contributions to the chemistry and biologyo fn ovel vinblastine analoguesi na n effort to improve cancert herapies. [1][2][3][60][61][62][63] Following its synthesis, 4-epi-vinblastine( 69)w as investigated for anticancer activity and demonstrated a % 12-fold loss in activities against L1210 (lymphocytic leukemia, IC 50 = 75 nm;S cheme 6B)a nd colorectal carcinoma( HCT116, IC 50 = 80 nm)c ell lines when compared to vinblastine (70). [58] Although this new analogue (69)d id not improve upon vinblastine'sa nticancer potency,i t is important to establisht he necessity of the C-4 stereochemistry of the vindoline moiety of vinblastine (70).…”