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. 2009 Mar 26;52(6):1701-11.
doi: 10.1021/jm801449a.

Discovery of 4-substituted methoxybenzoyl-aryl-thiazole as novel anticancer agents: synthesis, biological evaluation, and structure-activity relationships

Yan Lu  1 , Chien-Ming Li, Zhao Wang, Charles R Ross 2nd, Jianjun Chen, James T Dalton, Wei Li, Duane D Miller
Affiliations

Discovery of 4-substituted methoxybenzoyl-aryl-thiazole as novel anticancer agents: synthesis, biological evaluation, and structure-activity relationships

Yan Lu et al. J Med Chem. .

Abstract

A series of 4-substituted methoxybenzoyl-aryl-thiazoles (SMART) have been discovered and synthesized as a result of structural modifications of the lead compound 2-arylthiazolidine-4-carboxylic acid amides (ATCAA). The antiproliferative activity of the SMART agents against melanoma and prostate cancer cells was improved from muM to low nM range compared with the ATCAA series. The structure-activity relationship was discussed from modifications of "A", "B", and "C" rings and the linker. Preliminary mechanism of action studies indicated that these compounds exert their anticancer activity through inhibition of tubulin polymerization.

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Figures

Figure 1
Figure 1
Structures of LPA, ATCAA and SMART
Figure 2
Figure 2
Auto-dehydrogenation from thiazoline to thiazole compound 8f. At 0 day, NMR sample contained thiazoline and thiazole mixtures in CDCl3; ratio is about 3: 2. At 9th day, thiazoline compound was almost converted to thiazole compound 8f
Figure 3
Figure 3
ORTEP drawing of 8f with thermal ellipsoids depicted at 50 % probability level
Figure 4
Figure 4
Effect of 8f on tubulin assembly
Figure 5
Figure 5
SAR relationship of the SMART molecules
Scheme 1
Scheme 1
Reagents and conditions: (a) C2H5OH, H2O, r. t.; (b) Boc2O, 1 N NaOH, 1, 4-dioxane, H2O; (c) EDCI, HOBt, TEA, 3, 4, 5-trimethoxyaniline; (d) TFA, CH2Cl2.
Scheme 2
Scheme 2
Reagents and conditions: (a) MeOH / pH=6.4 phosphate buffer, r. t.; (b) EDCI, HOBt, TEA, 3, 4, 5-trimethoxyaniline; (c) CBrCl3, DBU.
Scheme 3
Scheme 3
Reagents and conditions: (a) MeOH/pH=6.4 phosphate buffer, r. t.; (b) EDCI, HOBt, NMM, HNCH3OCH3; (c) CBrCl3, DBU; (d) ArBr/BuLi or ArMgBr, THF; (e) HCl/HOAc; (f) MeOH/CH3COCl; (g) Fe/HOAc; (h) BBr3, CH2Cl2.
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References

    1. Cancer Facts & Figures. American Cancer Society; Atlanta, GA: 2008.
    1. Li W, Lu Y, Wang Z, Dalton JT, Miller DD. Synthesis and antiproliferative activity of thiazolidine analogs for melanoma. Bioorg Med Chem Lett. 2007;17:4113–7. - PubMed
    1. Li W, Wang Z, Gududuru V, Zbytek B, Slominski AT, Dalton JT, Miller DD. Structure-activity relationship studies of arylthiazolidine amides as selective cytotoxic agents for melanoma. Anticancer Res. 2007;27:883–888. - PubMed
    1. Lu Y, Wang Z, Li C-M, Li W, Dalton JT, Miller DD. Synthesis and biological evaluation of 2-arylthiazolidine-4-caboxylic acid amides for melanoma and prostate cancer. Abstracts of Papers, 234th ACS National Meeting, Boston, MA, United States. 2007 August 19-23;:MEDI-304.
    1. Gududuru V, Hurh E, Sullivan J, Dalton JT, Miller DD. SAR studies of 2-arylthiazolidine-4-carboxylic acid amides: a novel class of cytotoxic agents for prostate cancer. Bioorg Med Chem Lett. 2005;15:4010–4013. - PubMed

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