Antineoplastic Agents. 379. Synthesis of Phenstatin Phosphate^1a,

Abstract

A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (1b) directed at maintaining the (Z)-stilbene relationship of the olefin diphenyl substituents led to synthesis of a potent cancer cell growth inhibitor designated phenstatin (3b). Initially phenstatin silyl ether (3a) was unexpectedly obtained by Jacobsen oxidation of combretastatin A-4 silyl ether (1c --> 3a), and the parent phenstatin (3b) was later synthesized (6a --> 3a --> 3b) in quantity. Phenstatin was converted to the sodium phosphate prodrug (3d) by a dibenzyl phosphite phosphorylation and subsequent hydrogenolysis sequence (3b --> 3c --> 3d). Phenstatin (3b) inhibited growth of the pathogenic bacterium Neisseriagonorrhoeae and was a potent inhibitor of tubulin polymerization and the binding of colchicine to tubulin comparable to combretastatin A-4 (1b). Interestingly, the prodrugs were found to have reduced activity in these biochemical assays. While no significant tubulin activity was observed with the phosphorylated derivative of combretastatin A-4 (1d), phosphate 3d retained detectable inhibitory effects in both assays.

Eaton’s Reagent‐Mediated Domino π‐Cationic Arylations of Aromatic Carboxylic Acids to Iasi‐Red Polymethoxylated Polycyclic Aromatic Hydrocarbons: Products with Unprecedented Biological Activities as Tubulin Polymerization Inhibitors

“…It is worth mentioning that this two-step sequence represents a significant improvement over the first hemisynthesis of phenstatin (4 a) from com- bretastatin A4 (3 a) based on Jacobsen's oxidation. [24] The method constitutes a competitive approach to phenstatin and derivatives compared with the PPA-mediated Friedel-Crafts reaction.…”

Medicinal Chemistry and Chemical Biology of Diketopiperazine-Type Antimicrotubule and Vascular-Disrupting Agents

“…An investigation of the fluoro substitutions revealed that the 3-fluoro derivative (27) exhibited potent cytotoxic activity, and the 2,5-difluoro derivative (29) showed a 5.7-fold increase in potency (IC 50 value= 2.6 nM) compared with compound 7. This may reflect the unique properties of fluorinated organic compounds, including the improved entropies associated with the ligand binding to the target.…”

Synthesis and biological evaluation of boronic acid containing phenstatin analogues

“…2 Phenstatin (2a) is a synthetic tubulin assembly inhibitor developed by the same research group in 1998. 3 This compound is a benzophenone-type molecule and the functional groups on the two phenyl rings are similar to combretastatin A-4. 4 Based on the structures of both lead compounds, various benzophenone derivatives have been developed including aminobenzophenones (2b-c) 5,6 and isocombretastatin A (3).…”

“…A boron atom has a vacant orbital and interconverts with ease between the neutral sp 2 and the anionic sp 3 hybridization states, which generates a new stable interaction between a boron atom and a donor molecule through a covalent bond. 8 Therefore, it is expected that the boron atoms introduced into biologically active molecular frameworks would interact with a target protein not only through hydrogen bonds but also through covalent bonds, and this interaction might produce a potent biological activity.…”