Synthesis and Biological Properties of Benzothiazole, Benzoxazole, and Chromen-4-one Analogues of the Potent Antitumor Agent 2-(3,4-Dimethoxyphenyl)-5-fluorobenzothiazole (PMX 610, NSC 721648)

Aiello, Stefania; Wells, Geoff; Stone, Erica L.; Kadri, Hachemi; Bazzi, Rana; Bell, David R.; Stevens, Malcolm F. G.; Matthews, Chris; Bradshaw, Tracey D.; Westwell, Andrew D.

doi:10.1021/jm800418z

Cited by 306 publications

(112 citation statements)

References 25 publications

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“…Thus, the spectrum of activity of this bis-methyl ether extends to human cell lines derived from intractable colorectal carcinomas (CRC). A potent AhR ligand (K i ¼ 6.8 nmol/L), GW-610 is sequestered exclusively and rapidly by sensitive breast and CRC cells only (9,10).…”

Section: Introductionmentioning

confidence: 99%

CYP2S1 and CYP2W1 Mediate 2-(3,4-Dimethoxyphenyl)-5-Fluorobenzothiazole (GW-610, NSC 721648) Sensitivity in Breast and Colorectal Cancer Cells

Tan

Tiong

Muruhadas

et al. 2011

Molecular Cancer Therapeutics

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Both 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F-203; NSC 703786) and 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (GW-610; NSC 721648) are antitumor agents with novel mechanism(s). Previous studies have indicated that cytochrome (CYP) P450 1A1 is crucial for 5F-203 activity. In the present study, we investigated the functional role of 2 newly identified CYP P450 enzymes, CYP2S1 and CYP2W1, in mediating antitumor activity of benzothiazole compounds. We generated isogenic breast cancer (MDA-MB-468, MCF-7) and colorectal cancer (CRC; KM12 and HCC2998) cell lines depleted for CYP1A1, CYP2S1, or CYP2W1. The sensitivity of these cells to 5F-203 and GW-610 was then compared with vector control cells. 5F-203 exhibited potent activity against breast cancer cells, whereas GW-610 was effective against both breast and colorectal cancer cells. CYP1A1 was induced in both breast cancer and CRC cells, while CYP2S1 and CYP2W1 were selectively induced in breast cancer cells only following treatment with 5F-203 or GW-610. Depletion of CYP1A1 abrogated the sensitivity of breast cancer and CRC cells to 5F-203 and GW-610. Although depletion of CYP2S1 sensitized both breast cancer and CRC cells toward 5F-203 and GW-610, CYP2W1 knockdown caused marked resistance to GW-610 in CRC cells. Our results indicate that CYP-P450 isoforms, with the exception of CYP1A1, play an important role in mediating benzothiazole activity. CYP2S1 appears to be involved in deactivation of benzothiazoles, whereas CYP2W1 is important for bioactivation of GW-610 in CRC cells. Because CYP2W1 is highly expressed in colorectal tumors, GW-610 represents a promising agent for CRC therapy. Mol Cancer Ther; 10(10); 1982-92. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 99%

CYP2S1 and CYP2W1 Mediate 2-(3,4-Dimethoxyphenyl)-5-Fluorobenzothiazole (GW-610, NSC 721648) Sensitivity in Breast and Colorectal Cancer Cells

Tan

Tiong

Muruhadas

et al. 2011

Molecular Cancer Therapeutics

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“…Benzoxazoles are a class of heterocyclic compounds exhibiting therapeutical activities (Figure 2), such as, antifungal agents [38][39][40], cytotoxic compounds [41], as anti-inflammatory agents [42], as HIV-1 protease inhibitor [43], as an antibiotic [44], as CpIMPDH inhibitors [45], nonnucleoside HIV-1 reverse transcriptase inhibitors (NNRTI) [46], and antitumour agents [47].…”

Section: Benzoxazole Amides From Benzoylthioureasmentioning

confidence: 99%

Mechanistic Study on the Formation of Compounds from Thioureas

Laitonjam¹,

Nahakpam²

2018

Density Functional Calculations - Recent Progresses of Theory and Application

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Formation of 2-(N-arylamino)benzothiazole takes place, when N,N 0 -diphenylthioureas are treated with polymer-supported tribromide or with iodine-alumina as catalyst under solvent free conditions. However, when N-substituted-N 0 -benzoylthioureas are treated with polymer-supported tribromide or with iodine-alumina as catalyst either under various conditions or under solvent free conditions, decomposition takes place to give the respective benzamides and thiobenzamides. Mechanistic study of the formation of these compounds is studied using DFT calculations. It is found that electron donating group at the para-position of the aryl group of benzoylthiourea favors the formation of benzamide whereas the presence of electron withdrawing group at para-position of the aryl group of benzoylthiourea, formation of thiobenzamide takes place. When the catalyst is changed to diacetoxyiodobenzene (DIB) under similar reaction conditions, benzoxazole amides are formed; expected benzothiazoles or the decomposition products are not obtained. Mechanistic study of the reaction using DFT calculation again shows that the reaction followed through carbodiimide intermediate undergoes the formation of C-O bond in benzoxazole moiety, instead of the expected C-S bond formation of benzothiazole moiety via a sequential acylation and deacylation process.

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“…Various benzothiazole derivatives serve as drugs, dyes and industrial chemicals [1][2][3]. Benzothiazoleand its derivatives such as esters have also been reported as active against Gram-positive and Gram-negative bacteria Benzothiazole derivatives have also found to possess anticancer, antifungal and antibacterial activities [5,6]. 2-Aminobenzothiazole and a number of other aminobenzothiazole derivatives have been reported as muscle relaxants [7,8].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of N-(6-Arylbenzo[d]thiazole-2-acetamide Derivatives and Their Biological Activities: An Experimental and Computational Approach

et al. 2016

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Abstract:A new series of N-(6-arylbenzo [d]thiazol-2-yl)acetamides were synthesized by C-C coupling methodology in the presence of Pd(0) using various aryl boronic pinacol ester/acids. The newly synthesized compounds were evaluated for various biological activities like antioxidant, haemolytic, antibacterial and urease inhibition. In bioassays these compounds were found to have moderate to good activities. Among the tested biological activities screened these compounds displayed the most significant activity for urease inhibition. In urease inhibition, all compounds were found more active than the standard used. The compound N-(6-(p-tolyl)benzo[d]thiazol-2-yl)acetamide was found to be the most active. To understand this urease inhibition, molecular docking studies were performed. The in silico studies showed that these acetamide derivatives bind to the non-metallic active site of the urease enzyme. Structure-activity studies revealed that H-bonding of compounds with the enzyme is important for its inhibition.

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Synthesis and Biological Properties of Benzothiazole, Benzoxazole, and Chromen-4-one Analogues of the Potent Antitumor Agent 2-(3,4-Dimethoxyphenyl)-5-fluorobenzothiazole (PMX 610, NSC 721648)

Cited by 306 publications

References 25 publications

CYP2S1 and CYP2W1 Mediate 2-(3,4-Dimethoxyphenyl)-5-Fluorobenzothiazole (GW-610, NSC 721648) Sensitivity in Breast and Colorectal Cancer Cells

CYP2S1 and CYP2W1 Mediate 2-(3,4-Dimethoxyphenyl)-5-Fluorobenzothiazole (GW-610, NSC 721648) Sensitivity in Breast and Colorectal Cancer Cells

Mechanistic Study on the Formation of Compounds from Thioureas

Synthesis of N-(6-Arylbenzo[d]thiazole-2-acetamide Derivatives and Their Biological Activities: An Experimental and Computational Approach

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