2,5-Disubstituted-1,3,4-oxadiazoles/thiadiazole as surface recognition moiety: Design and synthesis of novel hydroxamic acid based histone deacetylase inhibitors

Rajak, Harish; Agarawal, Avantika; Parmar, Poonam; Thakur, Bhupendra Singh; Veerasamy, Ravichandran; Sharma, Prabodh Chander; Kharya, Murli Dhar

doi:10.1016/j.bmcl.2011.08.022

Cited by 99 publications

(40 citation statements)

References 24 publications

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“…Reactions were monitored by TLC using silica gel coated plates and different solvents solutions as the mobile phase. The synthesis of the compounds 1a and 1c (Rajak et al, 2011), 1b (Tenório, Carvalho, Pessanha, 2005), 1d (Grammaticakis, Sorbonne, 1959), 1e (Behnisch, Mietzsch, Schmidt, 1955), 1f (Oliveira et al, 2008b), 2a and 2c (Shih, Su, Wu, 2007), 2b (Maccioni et al, 2003) and 2e (Bilinski, Tyburczyk, Urban, 1961) was previously reported in the literature.…”

Section: General Proceduresmentioning

confidence: 90%

Synthesis and cytotoxicity evaluation of thiosemicarbazones and their thiazole derivatives

Braga

Fonseca

Ramos

et al. 2016

Braz. J. Pharm. Sci.

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The aims of this study were to synthesize a series of thiosemicarbazones and their thiazole derivatives, to investigate their cytotoxic activity against three human cancers and normal (Vero cells) cell lines, and to evaluate the pro-apoptotic potential of the most active compounds. Materials and Methods: The thiosemicarbazones were obtained by reacting an aromatic aldehyde with thiosemicarbazide (yield 71-96%), which were subjected to a cyclization with α-bromoacetophenone to yield the required thiazole heterocycles (yield 63-100%). All the synthesized compounds were screened at 50 µM concentration against three cell lines representing HL60 (promyelocytic leukemia), Jurkat (acute lymphoblastic leukemia), and MCF-7 (breast cancer). The pro-apoptotic effect was measured by flow cytometry as the percentage of cells with hypodiploid DNA. Results: Three thiazole compounds showed activity against at least one tumor cell line (IC 50 = 43-76 µM) and low cytotoxicity against Vero cells (IC 50 > 100 µM). The most active compound of this series induced 91% and 51% DNA fragmentation in HL60 and MCF-7 cell lines, respectively, suggesting that this compound triggered apoptosis in these cells. Conclusion: Among the synthesized compounds, one in particular was found to exert antiproliferative and pro-apoptotic activity on tumor cells and can be considered promising as a lead molecule for the design of new analogues with improved activity.Uniterms: Thiosemicarbazones/synthesis. Thiosemicarbazones/cytotoxic activity. Thiazoles/derivatives/ synthesis. Thiazoles/derivatives/cytotoxic activity. O estudo teve como objetivo a síntese de uma série de tiossemicarbazonas e seus derivados tiazólicos e a avaliação da atividade citotóxica contra três linhagens de células tumorais humanas e células normais (Vero), a fim de se avaliar o potencial pró-apoptótico dos compostos mais ativos. As tiossemicarbazonas foram obtidas por reação entre um aldeído aromático e tiossemicarbazida (rend. 71-96%), as quais foram submetidas à ciclização com α-bromoacetofenona, fornecendo os heterociclos tiazólicos desejados (rend. 63-100%). Todos os compostos sintetizados foram testados na concentração de 50 µM contra três linhagens de células tumorais: HL60 (leucemia promielocítica), Jurkat (leucemia linfoblástica aguda) e MCF-7 (câncer de mama). O efeito pró-apoptótico foi avaliado por citometria de fluxo como porcentagem de células com DNA hipodiplóide. Três compostos tiazólicos foram ativos contra, pelo menos, uma linhagem tumoral (CI 50 =43-76 µM), com baixa citotoxicidade contra células Vero (CI 50 > 100 µM). O composto mais ativo dessa série induziu fragmentação do DNA de 91% e 51% nas linhagens HL60 e MCF-7, respectivamente, sugerindo que este composto ativou a apoptose nessas células. Dentre os compostos sintetizados, um em particular apresentou atividade antiproliferativa e pró-apoptótica em células tumorais e pode ser considerado composto protótipo promissor na busca por novos análogos com atividade melhorada.

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Section: General Proceduresmentioning

confidence: 90%

Synthesis and cytotoxicity evaluation of thiosemicarbazones and their thiazole derivatives

Braga

Fonseca

Ramos

et al. 2016

Braz. J. Pharm. Sci.

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“…The diversity among the linkers has not been systematically explored, but nonetheless they exhibit limited chemical diversity surrounding chain-like alkyl linkers with various degrees of saturation and often include substituted aryl groups, dictated by the diameter and hydrophobicity of the tunnel region. The surface-recognition cap groups enjoy the widest range of chemotype tolerance, and have been the topic of extensive study in attempts to toggle potency [36,38,39], biodistribution [40], isoform selectivity [41], cardiotoxicity [42] and, more recently, tissue targeting [43]. …”

Section: Hdaci Pharmacophoric Modelmentioning

confidence: 99%

Targeted Cancer Therapy: Giving Histone Deacetylase Inhibitors All They Need To Succeed

2012

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Histone deacetylase inhibitors (HDACis) have now emerged as a powerful new class of small-molecule therapeutics acting through the regulation of the acetylation states of histone proteins (a form of epigenetic modulation) and other non-histone protein targets. Over 490 clinical trials have been initiated in the last 10 years, culminating in the approval of two structurally distinct HDACis – SAHA (vorinostat, Zolinza™) and FK228 (romidepsin, Istodax™). However, the current HDACis have serious limitations, including ineffectively low concentrations in solid tumors and cardiac toxicity, which is hindering their progress in the clinic. Herein, we review the primary paradigms being pursued to overcome these hindrances, including HDAC isoform selectivity, localized administration, and targeting cap groups to achieve selective tissue and cell type distribution.

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“…1,3,4-Oxadiazoles are an important class of heterocyclic compounds with a wide range of biological activities. [4][5][6] Among these, a few different substituted 1,3,4-oxadiazoles have exhibited potent antitumor activities. [7][8][9][10] Recently, a series of new 1,3,4-oxadiazole derivatives incorporating a pyridine moiety were synthesized and developed as potential telomerase inhibitors.…”

mentioning

confidence: 99%

Synthesis and Anticancer Evaluation of 1,3,4-Oxadiazoles, 1,3,4-Thiadiazoles, 1,2,4-Triazoles and Mannich Bases

Abdo

Kamel

2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of 5-(pyridin-4-yl)-N-substituted-1,3,4-oxadiazol-2-amines (3a-d), 5-(pyridin-4-yl)-N-substituted-1,3,4-thiadiazol-2-amines (4a-d) and 5-(pyridin-4-yl)-4-substituted-1,2,4-triazole-3-thiones (5a-d) were obtained by the cyclization of hydrazinecarbothioamide derivatives 2a-d derived from isonicotinic acid hydrazide. Aminoalkylation of compounds 5a-d with formaldehyde and various secondary amines furnished the Mannich bases 6a-p. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against six human cancer cell lines and normal fibroblast cells. Sixteen of the tested compounds exhibited significant cytotoxicity against most cell lines. Among these derivatives, the Mannich bases 6j, 6m and 6p were found to exhibit the most potent activity. The Mannich base 6m showed more potent cytotoxic activity against gastric cancer NUGC (IC50=0.021 µM) than the standard CHS 828 (IC50=0.025 µM). Normal fibroblast cells WI38 were affected to a much lesser extent (IC50>10 µM).

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2,5-Disubstituted-1,3,4-oxadiazoles/thiadiazole as surface recognition moiety: Design and synthesis of novel hydroxamic acid based histone deacetylase inhibitors

Cited by 99 publications

References 24 publications

Synthesis and cytotoxicity evaluation of thiosemicarbazones and their thiazole derivatives

Synthesis and cytotoxicity evaluation of thiosemicarbazones and their thiazole derivatives

Targeted Cancer Therapy: Giving Histone Deacetylase Inhibitors All They Need To Succeed

Synthesis and Anticancer Evaluation of 1,3,4-Oxadiazoles, 1,3,4-Thiadiazoles, 1,2,4-Triazoles and Mannich Bases

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