Ubiquitin E3 Ligases

(C21H22N2O4S) C, H, N

(C21H22N2O4S) C, H, N. (4-Amino-2-(4-tert-butylphenyl)thiazol-5-yl)(3,4,5-trimethoxyphenyl)methanone (3h) Following the general procedure, the crude residue, purified by flash chromatography using ethyl acetate/petroleum ether 4:6 (v/v) as eluent, furnished 3h as a yellow solid (54% yield); mp 66C68 C. components of the mitotic spindle.1 Microtubules are a dynamic cellular compartment in both neoplastic and normal cells. This dynamicity is characterized by the continuous turnover of -tubulin KLHL21 antibody heterodimers in the polymeric microtubules. The microtubule system is also important in other fundamental cellular processes, such as regulation of motility, cell signaling, formation and maintenance of cell shape, secretion, and intracellular transport.2 In the last decades, there has been a continuing interest in the discovery and development of novel small molecules able to inhibit tubulin polymerization.3 Numerous chemically diverse antimitotic agents, many of which are natural products, interact specifically with tubulin. 4 Among the naturally occurring derivatives, combretastatin A-4 (CA-4, 1, Chart 1), isolated from the bark of the South African tree Cell Growth Inhibitory Effects of Compounds 1 and 3a?o assays with HUVECs. CHEMISTRY The general synthesis of 2-aryl/heteroaryl-4-amino-5-(3,4,5-trimethoxybenzoyl)thiazoles 3aCo is outlined in Scheme 1. These molecules were prepared by a one-step efficient synthetic procedure, starting from an easily accessible common intermediate 5.8 This latter compound was obtained in good yield by a one-pot three-step ARP 100 sequential procedure, starting from dimethyl cyanodithiocarbonate 4, which was reacted successively with sodium sulfide, 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone and potassium carbonate.11 The Pd2dba3-catalyzed, Cu(I)Tc-mediated coupling of thiazole-2-thiomethyl ether 5 with the appropriate aryl/heteroaryl boronic acid, in the presence of TFP, furnished the 2-aryl/heteroaryl substituted thiazoles 3aCo in high yields, avoiding the protection/deprotection sequence of the amino group at the 4-position of the thiazole ring.12 Open in a separate window Scheme 1Antiproliferative Activities The 2-aryl/heteroaryl-4-amino-5-(3,4,5-trimethoxybenzoyl)thiazoles 3aCo were evaluated for their antiproliferative activity against a panel of six human tumor cell lines and compared with reference compound 1. As shown in Table 1, the antiproliferative activities of the tested compounds were generally more pronounced against HeLa and MCF-7 cells as compared with the other cell lines. With the exception of MCF-7 cells, the 3-thienyl derivative 3b was the most active compound in this series, exhibiting IC50 values ranging from 2.4 ARP 100 to 78 nM against five of the six cancer cell lines and an IC50 of 210 nM against the A549 cells. Moreover, with the MCF-7 and HT-29 cells, compounds 3aCc, 3eCf, and 3k were more potent than 1, with IC50 values in the single- or double-digit nanomolar range. Compounds 3b and 3e showed comparable potency to 1 1 against the HeLa cells. Of the 15 tested compounds, 3aCb, 3e, and 3k ARP 100 possessed the highest overall potency, with IC50 values of 2.4C140 nM against five of the six cancer cell lines and IC50 values of 200C700 nM against the A549 cells. With the exception of MCF-7 and HT-29 cells, reference compound 1 possessed the highest potency in four of the six cell lines tested. The bioisosteric replacement of the phenyl ring of compound 3a with the 3-thienyl group (3b) produced a 1.5- to 3-fold increase of potency against A549, Jurkat, and HeLa cells, while the differences between 3a and 3b were minimal in HL-60 and HT-29 cells. Only in MCF-7 cells was 3b less active than 3a (IC50 values of 51 and 2.2 nM, respectively). Excluding the A549 cells, compounds 3a and 3b had IC50 values ranging from 24 to 80 nM against the cell lines, compared with a range of 1C3100 nM obtained with 1. The data shown in Table 1 demonstrated the importance of substituents on the phenyl ring at the 2-position of the thiazole system for activity and selectivity against the different cancer.