In:
Helvetica Chimica Acta, Wiley, Vol. 81, No. 5-8 ( 1998-01), p. 1023-1037
Abstract:
7‐ O ‐Substituted analogs of deaminodeoxycolchinol thiomethyl ether were synthesized and evaluated for their inhibitory effects on tubulin polymerization in vitro . Ketone 9 , a key compound in this study, was derived from thiocolchicone 6 by reaction with aniline. Reaction of compound 6 with MeNH 2 or BuNH 2 gave tetracyclic lactams 7 and 8 , respectively. Optically active alcohols 11a and 11b were obtained from racemic 11 by chemical resolution including a separation of the comphanate diastereoisomers 12a and 12b , followed by basic hydrolysis. The (a R ,7 R )‐configuration of 12b was verified by X‐ray crystallographic analysis. Almost all racemic and optically active 7‐ O ‐acyl or 7‐ O ‐aroyl compounds had strong inhibitory effects on the tubulin polymerization reaction, with IC 50 values from 1.7 to 5.1 μM. A few agents, such as the lactams 7 and 8 , the camphanates 12a and 12b , the cyclohexanecarboxylates 19a and 19b , and, most notably, the (7 S )‐benzoate 15a , had negligible effects on polymerization, yielding IC 50 values greater than 40μ M . Ketone 9 showed strong inhibition of tubulin polymerization comparable to that of thiocolchicone ( 6 ). Optically active alcohol 11a and acyl esters 13a and 14a with a (7 S )‐configuration were more active than the (7 R )‐esters 13b and 14b . However, the esters 15a – 17a with a (7 S )‐configuration were less active than the (7 R )‐isomers 15b – 17b , in which the (7 R )‐benzoate 15b was at least 15‐fold more inhibitory than the (7 S )‐isomer 15a . For the most part, the agents causing strongest inhibition of polymerization also caused the greatest inhibition of [ 3 H]colchicine binding. NMR and optical rotatory data indicate that, in polar solvents, the equilibrium in esters with a 7‐ O ‐aroyl substituent, i.e. , 15a , b , 16a , b , and 17a , b , is reversed from (a S ) to (a R ) or from (a R ) to (a S ), as compared to nonpolar solvents.
Type of Medium:
Online Resource
ISSN:
0018-019X
,
1522-2675
DOI:
10.1002/hlca.v81:5/8
DOI:
10.1002/hlca.19980810516
Language:
English
Publisher:
Wiley
Publication Date:
1998
detail.hit.zdb_id:
74-7
detail.hit.zdb_id:
1475013-2
Permalink