SYNTHESIS AND CYCLIZATION OF 1-(<i>N</i>-NITROAMIDINO)THIOUREAS TO 2,4-DIAMINOTHIAZOLES

Binu, R.; Thomas, K. Kurien; Jenardanan, G. C.; Rajasekharan, K. N.

doi:10.1080/00304949809355265

Cited by 21 publications

(12 citation statements)

References 2 publications

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“…The thiourea derivatives [5][6][7] (6a-k) provide four ring atoms for the thiazole ring construction and thus act as [CANACAS] synthons. The remaining carbon of the thiazole is sourced from 2-(2-bromoacetyl)-1-methyl-1H-benzimidazole.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of [2,4‐bis(arylamino)thiazol‐5‐yl](1‐methyl‐1H‐benzimidazol‐2‐yl)methanones

Reji

Rajasekharan

2009

Journal of Heterocyclic Chem

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magnified image[2,4‐Bis(arylamino)thiazol‐5‐yl]‐(1‐methyl‐1H‐benzimidazol‐2‐yl)methanones, as the analogs of the cytotoxic marine alkaloid dendrodoine, are synthesized and characterized by elemental analysis, IR, NMR, and Mass spectral data. The thiourea derivatives provide four ring atoms for the thiazole ring construction and thus act as [CNCS] synthons. The remaining carbon of the thiazole is sourced from 2‐(2‐bromoacetyl)‐1‐methyl‐1H‐benzimidazole. This [4+1] heterocyclization reaction is adopted for the synthesis of novel 1‐methyl‐1H‐benzimidazole derivatives. J. Heterocyclic Chem., (2009).

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Section: Resultsmentioning

confidence: 99%

“…In this context, the 2-amino-5-ketothiazole synthesis developed by us [5][6][7] appeared promising. A variety of amino substituents could be placed on C-2 and C-4 carbons of the thiazole ring by choosing the appropriate thiourea synthon and the 5-keto substituent could be accessed through a variety of a-haloketones.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of [2,4‐bis(arylamino)thiazol‐5‐yl](1‐methyl‐1H‐benzimidazol‐2‐yl)methanones

Reji

Rajasekharan

2009

Journal of Heterocyclic Chem

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“…DAT1 was synthesized as reported earlier (19). Taxol (paclitaxel), PIPES, GTP, EGTA, DTNB, and Sephadex G-50 were from Sigma.…”

Section: Methodsmentioning

confidence: 99%

Reversible Action of Diaminothiazoles in Cancer Cells Is Implicated by the Induction of a Fast Conformational Change of Tubulin and Suppression of Microtubule Dynamics

Thomas¹,

Thamkachy²,

Sivakumar³

et al. 2014

Molecular Cancer Therapeutics

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Diaminothiazoles are novel cytotoxic compounds that have shown efficacy toward different cancer cell lines. They show potent antimitotic and antiangiogenic activity upon binding to the colchicine-binding site of tubulin. However, the mechanism of action of diaminothiazoles at the molecular level is not known. Here, we show a reversible binding to tubulin with a fast conformational change that allows the lead diaminothiazole DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino)thiazole] to cause a reversible mitotic block. DAT1 also suppresses microtubule dynamic instability at much lower concentration than its IC 50 value in cancer cells. Both growth and shortening events were reduced by DAT1 in a concentration-dependent way. Colchicine, the long-studied tubulin-binding drug, has previously failed in the treatment of cancer due to its toxicity, even though it generates a strong apoptotic response. The toxicity is attributable to its slow removal from the cell due to irreversible tubulin binding caused by a slow conformational change. DAT1 binds to tubulin at an optimal pH lower than colchicine. Tubulin conformational studies showed that the binding environments of DAT1 and colchicine are different. Molecular dynamic simulations showed a difference in the number of H-bonding interactions that accounts for the different pH optima. This study gives an insight of the action of compounds targeting tubulin's colchicine-binding site, as many such compounds have entered into clinical trials recently.

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“…HCT 116 (human colon carcinoma) was a kind gift from Dr Bert Vogelstein of The Johns Hopkins University School of Medicine, Baltimore, U.S.A. L929 (mouse connective tissue fibrocarcoma) was from ATCC, Manassas, U.S.A. Antibodies, paclitaxel, vinblastine, podophyllotoxin, colchicine and other fine chemicals were from Sigma, St Louis, U.S.A. DAT1 was synthesized by adopting an improved solid phase approach (unpublished results) of the solution phase synthesis as reported earlier (Rajasekharan et al, 1986;Binu et al, 1998).…”

Section: Methodsmentioning

confidence: 99%

“…This compound was reported earlier to have cytotoxicity (Helbecque et al, 1987), but was not explored further. A series of synthetic diaminoaroylthiazole analogues of dendrodoine (Rajasekharan et al, 1986;Binu et al, 1998) were synthesized, and DAT1 (4-amino-5-benzoyl-2-(4-methoxyphenylamino)thiazole) ( Figure 1) was selected in a preliminary screen based on its cytotoxic activities (Patent Application no. PCT Int.…”

Section: Introductionmentioning

confidence: 99%

4‐Amino‐5‐benzoyl‐2‐(4‐methoxyphenylamino)thiazole (DAT1): a cytotoxic agent towards cancer cells and a probe for tubulin‐microtubule system

Sengupta

Smitha

Thomas

et al. 2005

British J Pharmacology

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1 Microtubule binding drugs are of special interest as they have important roles in the modulation of cellular functions and many of them act as anticancer agents. 4-Amino-5-benzoyl-2-(4-methoxyphenylamino)thiazole (DAT1) was identified as one of the active compounds from a series of diaminoketothiazoles in a cell-based screening assay to discover cytotoxic compounds. 2 DAT1 shows cytotoxicity with GI 50 values ranging from 0.05 to 1 mM in different malignant cell lines with an average value of 0.35 mM. It blocks mitosis in the prometaphase and metaphase stages. In HeLa cells, DAT1 blocks the spindle function by disturbing spindle microtubule and chromosome organization. 3 The drug also inhibits assembly of brain microtubules and binds tubulin specifically at a single site with induction of fluorescence. The dissociation constant of DAT1 binding to tubulin was determined as 2.971 mM at 241C. The binding site of DAT1 on tubulin overlaps with that of the conventional colchicine-binding site. 4 DAT1 can thus be considered as a lead compound of a new class of small molecules and this study can be used as a step to develop potent antimitotic agents for the control of cytoskeletal functions and cell proliferation. It would also be an interesting probe for the structure-function studies of tubulinmicrotubule system.

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SYNTHESIS AND CYCLIZATION OF 1-(N-NITROAMIDINO)THIOUREAS TO 2,4-DIAMINOTHIAZOLES

Cited by 21 publications

References 2 publications

Synthesis of [2,4‐bis(arylamino)thiazol‐5‐yl](1‐methyl‐1H‐benzimidazol‐2‐yl)methanones

Synthesis of [2,4‐bis(arylamino)thiazol‐5‐yl](1‐methyl‐1H‐benzimidazol‐2‐yl)methanones

Reversible Action of Diaminothiazoles in Cancer Cells Is Implicated by the Induction of a Fast Conformational Change of Tubulin and Suppression of Microtubule Dynamics

4‐Amino‐5‐benzoyl‐2‐(4‐methoxyphenylamino)thiazole (DAT1): a cytotoxic agent towards cancer cells and a probe for tubulin‐microtubule system

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