Deaminocolchinyl Methyl Ether: Synthesis from 2,3,4,4′‐Tetramethoxybiphenyl‐2‐carbaldehyde. Comparison of antitubulin effects of deaminocolchinyl methyl ether and dehydro analogs

Abstract

Synthesis of deaminocolchinyl methyl ether 9 was achieved from tetramethoxy-substituted biphenyl-2-carbaldehyde 12 via tricyclic ketone 20 and 5,6-didehydro congener 11. Compound 9 was identical in every respect with material prepared from colchicine uiu 6,7-didehydro congener 10. Measuring inhibition of tubulin polymerization in vitro showed compounds 4, 5, and 9-11 of the alloseries of colchicinoids to be particularly potent inhibitors.Introduction. -A large number of synthetic and natural compounds bind to the protein tubulin and, in so doing, inhibit its polymerization in vitro [l]. This property accounts for many of the effects observed when cells are treated with this class of agents, most notably failure of mitotic spindle formation and dissolution of the interphase microtubule network. This disruption of microtubules is probably responsible for the therapeutic properties of antimitotic agents. The majority of compounds which inhibit tubulin polymerization also, despite remarkably diverse structures, competitively inhibit the binding of radiolabeled colchicine to tubulin. This implies that, despite their structural diversity, they share features that allow them to bind at a common site on the protein. The most thoroughly studied member of this class of drugs is colchicine ( = ( S ) -N-(5,6,7,9-tetrahydro-l,2,3,l0-tetramethoxy-9-oxobenzo[a]heptalen-7-yl)acetamide; 1, R' = CH,, R2 = CH,CONH, R3 = CH,O).Because of the antineoplastic potential of agents which inhibit microtubule assembly, a thorough understanding of the colchicine binding site is important. One approach to this problem is evaluation of antitubulin properties of analogs of active drugs. For example, virtually all colchicinoids summarized in structure 1, as well as the dehydro analog 2 [2], inhibit tubulin polymerization and the growth of tumor cells in vitro and, in some cases, in vivo. More drastic changes in the colchicine molecule have surprisingly little apparent effect on most of these inhibitory properties. Complete elimination of ring B yields an antimitotic compound binding at the colchicine site (2-methoxy-5-(2',3',4-trimethoxyphenyl)cyclohepta-2,4,6-trien-l-one (3)) [3] [4]. Conversion of the 7-membered 2-substituted cycloheptatrienone moiety (ring C) to a 6-membered phenyl ring yields compounds more potent than colchicine as polymerization inhibitors (allocolchicine (4) and N-acetylcolchinyl methyl ether 5) [3] [5].

The Non-Grid Technique for Modeling 3D QSAR Using Self-Organizing Neural Network (SOM) and PLS Analysis: Application to Steroids and Colchicinoids

“…From many different compounds which have been tested as potential ligands binding tubulin the series characterized by a various degree of similarity to a parent colchicine structure, as reported in a single publication [63], has been selected for this analysis. The inhibitory effect on tubulin polymerization is given in Table 11.…”

“…data according to[63])The inhibitory effect of colchicinoid compounds analyzed on tubulin polymerization, Downloaded by [Chulalongkorn University] at 08:19 26 December 2014 …”

One-Pot Synthesis of Phenol Derivatives by the Novel Intramolecular Alder–Rickert Reaction: Effects of Aryl Substituent at the 3-Position of Cyclohexenone Derivatives on Reactivity

“…2). Moreover, products 8 in this sequence would possess a 4-phenylindane unit which is utilized as a privileged platform in medicinal chemistry [5][6][7][8] and observed in several natural products.…”

“…2). Moreover, products 8 in this sequence would possess a 4-phenylindane unit which is utilized as a privileged platform in medicinal chemistry [5][6][7][8] and observed in several natural products. [9][10][11] Based upon the aforementioned working hypothesis, we examined the consecutive Lewis acid-catalyzed enolization and intramolecular AlderRickert reactions employing 3-aryl cyclohexenone derivatives.…”

Self-organizing neural network for modeling 3D QSAR of colchicinoids.

“…In the present paper a new method based on self-organizing neural networks has been developed to obtain a quantitative 3D QSAR model describing a series of colchicinoids described by Boye et al [14].…”