Antitumor Benzothiazoles. 3. Synthesis of 2-(4-Aminophenyl)benzothiazoles and Evaluation of Their Activities against Breast Cancer Cell Lines in Vitro and in Vivo

Abstract

A new series of 2-(4-aminophenyl)benzothiazoles substituted in the phenyl ring and benzothiazole moiety has been synthesized by simple, high-yielding routes. The parent molecule 5a shows potent inhibitory activity in vitro in the nanomolar range against a panel of human breast cancer cell lines, but is inactive (IC50 > 30 microM) against other cell types: activity against the sensitive breast lines MCF-7 and MDA 468 is characterized by a biphasic dose-response relationship. Structure-activity relationships derived using these cell types has revealed that activity follows the heterocyclic sequence benzothiazole > benzoxazole >> benzimidazole and that 2-(4-aminophenyl)benzothiazoles bearing a 3'-methyl- 9a, 3'-bromo- 9c, 3'-iodo- 9f, and 3'-chloro-substituent 9i are especially potent and their activity extends to ovarian, lung, and renal cell lines. Four compounds have been evaluated in vivo against human mammary carcinoma models in nude mice. Compound 9a showed the most potent growth inhibition against the ER+ (MCF-7 and BO) and ER- (MT-1 and MT-3) tumors. Our efforts to identify a pharmacological mechanism of action for these intriguing compounds have not, as yet, been successful.

Retracted: Synthesis and Cytotoxic Activity of 2‐Anilinopyridine‐3‐Acrylamides as Tubulin Polymerization Inhibitors

“…[10][11][12][13] Various modified arylbenzothiazoles and substituted 2-aminobenzothiazoles are also known to possess significant anticancer activity both in vitro and in vivo. [14][15][16][17][18] Phenylcinnamide derivative 4 [19] induced G 2 /M-phase cell-cycle arrest and cell death in cancer cell lines at low micromolar concentrations. The cytotoxic effect of this compound was found to be exerted through the disruption of microtubule dynamics.…”

Synthesis and cytotoxic activity of new pyrazolo[1,5-a]pyrimidines and determination of pyrimidine regiospecific ring formation with 2D NMR

“…[5][6][7] Compound 2 was reported to be an effective anti-tumour agent and a scaffold to adenosine (ATP) binding receptor in several kinases. 6 Moreover, various (3,4-dimethoxyphenyl)-5-fluorobenzothiazole (PMX610) [12][13][14][15] are famous with their potency that enable them to be effective anti-cancer agents. Based on these findings, and as a continuation of previous work, [16][17][18][19][20] we synthesized new expected drug hybrid of two active moieties pyrazolopyrimidine and benzothiazole or oxazole.…”

Synthesis and In vitro Antimicrobial Activity of Novel 2-(4-(Substituted-carboxamido)benzyl / phenyl)benzothiazoles

“…5 The compounds possess benzothiazole nucleus in their structure are involved in research aimed at evaluating new chemotherapeutically active agents: such as antimicrobial [6][7][8][9] a topical carbonic anhydrase inhibitor, 10 a cyclooxygenase inhibitor, 11 antitubercular, 12,13 antinematode, 14 a dual inhibitor of thromboxane A 2 synthetase and 5-lipoxygenase 15 , a selective and reversible inhibitor of monoamine oxidase type A (MAO-A), 16 antiallergic, 17 multi-drug resistance cancer cell activities with inhibiting activity on eukaryotic topoisomerase II enzyme in cell-free system [18][19][20] and antitumor agents. [21][22][23] Currently, a new series of benzothiazoles have been synthesized as antitumor agents and showed potent inhibitory activity against human breast cancer cell lines in vitro and in vivo. 21 Among them, lysyl-amide of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (Formula 1) had been selected for phase 1 clinical evaluation.…”

“…[21][22][23] Currently, a new series of benzothiazoles have been synthesized as antitumor agents and showed potent inhibitory activity against human breast cancer cell lines in vitro and in vivo. 21 Among them, lysyl-amide of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (Formula 1) had been selected for phase 1 clinical evaluation. 22 In the last years, we reported the synthesis of several 2-substitutedbenzothiazole derivatives as the anti- microbial agents 7,8 as seen in Formula 2.…”