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. 2011 Dec 8;2(12):948-952.
doi: 10.1021/ml200236a.

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

Hiroaki Gotoh  1 , Katharine K Duncan, William M Robertson, Dale L Boger
Affiliations

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

Hiroaki Gotoh et al. ACS Med Chem Lett. .

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 (IC(50) = 800 pM, HCT116) and vinblastine-resistant tumor cell lines (IC(50) = 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.

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Figures

Figure 1
Figure 1
Natural products.
Figure 2
Figure 2
C10 substituent effects.
Figure 3
Figure 3
C12 substituent effects.
Figure 4
Figure 4
10′-Fluorovincristine and 10′-fluorovinblastine.
Figure 5
Figure 5
Space-filling model of the 10′-fluoro binding site of 10b (R = F, left) generated by adding the fluorine substituent to the X-ray structure of tubulin-bound vinblastine (R = H, right). Comparison models of 7b–9b (R = Cl, Br, and I) are provided in Figure S2 in the Supporting Information and illustrate the unique fit for 10b (R = F) and the increasing destabilizing steric interactions at this site as the substituent size progressively increases.
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