10′-Fluorovinblastine and 10′-Fluorovincristine: Synthesis of a Key Series of Modified Vinca Alkaloids

Abstract

A study on the impact of catharanthine C10 and C12 indole substituents on the biomimetic Fe(III)-mediated coupling with vindoline led to the discovery and characterization of two new and substantially more potent derivatives, 10’-fluorovinblastine and 10’-fluorovincristine. In addition to defining a pronounced and unanticipated substituent effect on the biomimetic coupling, fluorine substitution at C10’, which minimally alters the natural products, was found to uniquely enhance the activity 8-fold against both sensitive (IC50 = 800 pM, HCT116) and vinblastine-resistant tumor cell lines (IC50 = 80 nM, HCT166/VM46). As depicted in the X-ray structure of vinblastine bound to tubulin, this site resides at one end of the upper portion of the T-shaped conformation of the tubulin-bound molecule, suggesting the 10’-fluorine substituent makes critical contacts with the protein at a hydrophobic site uniquely sensitive to steric interactions.

Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer–dimer interface

“…6). Substitution of the isoindoline was well tolerated and the series displayed a trend where electron-donating substituents (30,(35)(36)(37)(38)(39) proved slightly more potent than compounds bearing electron-withdrawing substituents (31)(32)(33)(34). Within the former series, further alkylation (37)(38)(39) or acylation (40-53) of the aniline 36 was well tolerated.…”

“…This behavior of BODIPY-vinblastine allows fluorescent measurements of coincubation solutions to establish the percentage displacement of probe by a competitive binding site ligand. Tubulin was incubated with BODIPY-vinblastine and a representative range of competitive ligands including vinblastine, 10′-fluorovinblastine [71, a previously reported vinblastine analog with 10-fold improved functional activity (35)], the potent compound 28, and three ultrapotent C20′ urea analogs (58, 60, and 61) reported here. At the concentration tested, vinblastine displaced 31% of the BODIPY-vinblastine bound to tubulin (Fig.…”

“…One general observation made in these studies is that, although modifications to the key structural features of vinblastine typically result in reductions in biological activity, addition of structural features can substantially improve them (20,21,35,36). This includes not only our demonstration of the impact of the addition of an indole C10′ fluorine substituent (35) and the incorporation of the C20′ ethyl group into a benign more complex cis-fused C15′-C20′ six-membered ring (36), but also the discovery of the improved activity of C20′ urea replacements for the tertiary alcohol (20,21). Herein, we reported the discovery of compounds in this latter series that are now a stunning 100-fold more potent than vinblastine.…”

Synthesis and biological evaluation of C-13′ substituted 7′- homo -anhydrovinblastine derivatives

“…This latter position was diversely functionalized and many analogues of vinblastine 1, vincristine 2, vinorelbine 3 and vinflunine 4 were elaborated. [6][7][8] The evaluation of the biological activities of these vinca derivatives showed that only small uncharged functional groups can be tolerated on C-12 0 (methyl, ethyl, nitrile, ethynyl and small thioethers) to retain or increase the cytotoxicity. For example, ALB-109564 5, 9 an analogue of vinblastine carrying a methylthioether on C-12 0 , was found more cytotoxic than vinorelbine 3 on P388 cell lines.…”

Synthesis of a Potent Vinblastine: Rationally Designed Added Benign Complexity

“…9 Among the most significant of the observations made to date in these studies is that while removal of individual substituents or key structural components of the natural products typically results in reductions in biological activity, 8–14 addition of structural features can substantially improve biological properties. 15,16 As a result of our demonstration of the importance of the addition of a key indole C10′ substituent (10′-fluorovinblasine) 15 and with the discovery of the remarkable impact of select C20′ alcohol replacements (C20′ ureas), 16 it appeared that the spatial placement of the indole at one end of velbanamine and the C20′ ethyl group at the other are two especially important features of the structure. The X-ray structure of tubulin-bound vinblastine 5 (Figure 2) indicates both fit into well-defined protein pockets on the tubulin α and β subunits, respectively, deeply embedded in the tubulin binding site with each occupying corners of a T-shaped bound conformation of vinblastine.…”