Synthesis and tubulin binding of novel C-10 analogs of colchicine

Abstract

A series of novel C-10 derivatives of colchicine have been prepared and evaluated for inhibition of in vitro microtubule assembly and of [3H]colchicine binding to tubulin. The C-10 substituent of colchicine was replaced by halogens, alkyl and alkoxy groups, and hydrogen. Many of these compounds are available by nucleophilic substitution of 10-fluoro-10-demethoxycolchicine (9) without concomitant formation of ring contraction products. Compound 9 is prepared by reaction of (diethylamino)sulfur trifluoride with colchiceine. Unlike most reactions of colchiceine, the colchicine rather than the isocolchicine regiosiomer is the predominant product of this reaction. It was found that modification of the C-10 substituent of colchicine had a relatively minor effect on the potency of the colchicinoids. The electronic nature of the substituent had no significant effect on the efficacy of the compound, indicating that hydrogen bonding or polar interactions between the C-10 substituent of colchicinoids and an amino acid in the colchicine binding site on tubulin are not present in the colchicine-tubulin complex. A decrease in activity was observed with increasing length of the alkyl chain bonded to the C-10 position, but potency was less affected when the alkyl groups were positioned in close proximity to the C-10 carbon of the tropone ring. It is concluded that the steric rather than the electronic properties of the C-10 substituent are the predominant determinants of activity in this series.

Diversity Oriented Synthesis of Allocolchicinoids with Fluoro and/or Oxygen Substituent(s) on the C‐Ring from a Single Common Intermediate

“…The reaction mixture was stirred overnight at 100°C. 19 The reaction mixture was extracted with EtOAc (3 × 3.0 mL).…”

“…[13] Furthermore, modification or absence of the Bring was reported to retain potent antimitotic activity. Therefore, in this study, we report the diversity-oriented synthesis of a range of C-ring fluorinated allocolchicinoids [(±)-IV and (±)-V], which have been rarely reported to date, [18,19] and C-ring oxygenated derivatives that include known N-acetyl-tating the preparation of a diverse number of fluoro derivatives. [15] In addition, kreysigine (6), [16] which shows muscle relaxant activity, and some other congeners, such as jerusalemine (7), [17] are also found in nature.…”

Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities Are Predicted for C-2 Analogues in the Colchicine Site

“…11,14 The ester chain in mode I overlaps with the C-10 substituents of colchicine and the SAR of colchicine C-10 analogs also shows that increasing length of the alkyl chain causes a concomitant decrease in activity. 25 We propose that the deeper burial of mode I ligands is more disruptive to the association of α- and β-tubulin subunits than is binding with mode II. We are continuing design and development of additional JG-03-14 ( 1 ) analogs by focusing on other positions of the pyrrole core as we attempt to gain a full view of the SAR.…”

Expression and transcriptional activities of nuclear receptors involved in regulation of drug-metabolizing enzymes are not altered by colchicine: Focus on PXR, CAR, and GR in primary human hepatocytes

“…On the other hand, EIN and COL differ only in substitution at the O-10 atom (-H for EIN vs.-CH 3 for COL; for structures see Figure 4). The ability of EIN to disrupt microtubules is an order of magnitude lower than that of COL (Edstrom et al, 1979;Staretz and Hastie, 1993). Therefore, the finding that EIN does not affect expression and transcriptional activities of PXR, CAR, and GR receptors favors the hypothesis of cytoskeleton-dependent GR-PXR/CAR-P450s signaling.…”