Evaluation of the thiosemicarbazones of some aryl alkyl ketones and related compounds for anticonvulsant activities

Dimmock, J. R.; McColl, J. D.; Wonko, SL; Thayer, RS; Hancock, D. S.

doi:10.1016/0223-5234(91)90148-g

Cited by 33 publications

(34 citation statements)

References 5 publications

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“…A previous investigation revealed that the second order rate constants between a biomimetic thiol and a cluster of Mannich bases of acyclic ketones 1 was approximately 240 times faster than the corresponding enones 2 when the same substituents are in the aryl rings [19]. However while some of the acyclic Mannich bases have cytotoxic and anticancer properties [20], respiratory depression was noted in low doses for many of these types of compounds when they were administered to mice [21]. The acyclic enones are flexible molecules and therefore able to assume a variety of different shapes, some of which may have antineoplastic properties while others are responsible for the unwanted toxicity.…”

Section: 5-bis(benzylidene)-4-piperidonesmentioning

confidence: 99%

1,5-Diaryl-3-oxo-1,4-pentadienes: A Case for Antineoplastics with Multiple Targets

Das

Sharma²,

Dimmock³

2009

CMC

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A number of organic molecules which contain the 1,5-diaryl-3-oxo-1,4-pentadienyl group, referred to hereafter as the dienone moiety, have antineoplastic properties. Emphasis is made on the attachment of this structural moiety to several molecular scaffolds, namely piperidines, Nacylpiperidines, cycloalkanes and 3,4-dihydro-1H-napthalenes. Many of these compounds are potent cytotoxins having micromolar and nanomolar IC 50 values towards a wide range of neoplastic and transformed cells. On occasions, greater toxicity towards neoplasms than normal cells has been demonstrated. A number of these compounds have in vivo anticancer properties and in general excellent tolerability in rodents is demonstrated. The way in which a number of physicochemical properties such as redox potentials, torsion angles, atomic charges and logP values govern cytotoxic potencies are presented. The importance of the shapes of different compounds as determined by molecular modeling in contributing to antineoplastic properties is outlined. Arguments are presented in favour of designing antineoplastics which have multiple sites of action in contrast to those bioactive molecules which have only one molecular target. A number of compounds which possess the dienone group have different modes of action some of which are chronicled in this review, such as inducing apoptosis, affecting respiration in mitochondria, inhibiting macro-molecular biosynthesis and both inhibiting and stimulating certain enzymes. Other important properties of these compounds are discussed including their anti-angiogenic, MDR-revertant and antioxidant properties. It is hoped that this eulogy of the importance of the dienone group will encourage researchers to consider incorporating this structural unit into candidate cytotoxins in the future.

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Section: 5-bis(benzylidene)-4-piperidonesmentioning

confidence: 99%

1,5-Diaryl-3-oxo-1,4-pentadienes: A Case for Antineoplastics with Multiple Targets

Das

Sharma²,

Dimmock³

2009

CMC

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“…General procedure: synthesis of thiazole heterocycles (Dimmock et al, 1991) To a solution of 1 equiv. of thiosemicarbazones (1a-1f) in isopropyl alcohol was added 1 equiv.…”

Section: General Proceduresmentioning

confidence: 99%

“…Thiosemicarbazones and their thiazole heterocyclic derivatives are of great importance in pharmacology due to their broad range of biological activities, such as anticonvulsant, antimicrobial, and antiparasitic activities (Gaikwad, Patil, Bobade, 2013;Souza et al, 2013;Bharti et al, 2010;Siddiqui et al, 2009;Oliveira et al, 2008a;Souza, 2005;Dimmock et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

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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“…The PTK chosen was fyn kinase since a previous study from this laboratory showed that the Mannich base 1 stimulated this enzyme [7]. However murine toxicity was noted with 1 [7] and other acyclic Mannich bases (3-aminoketones) [8,9], suggesting that pursuit of this concept should proceed using less toxic analogues. On the other hand 2, which is a 4-piperidone (a cyclic 3-aminoketone) and contains arylmethylene groups, as well as related Nacyl analogues, are well tolerated in mice [10,11].…”

Section: Introductionmentioning

confidence: 99%

N–Acyl–3,5–bis(arylidene)-4-piperidones and related compounds which stimulate fyn kinase

Das

Selvakumar

Sharma

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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This study is part of a long term project designed to explore the hypothesis that stimulation of cancer cells followed by treatment with one or more cytotoxic agents may create greater damage to tumours than to the corresponding normal tissues. The aim of the present investigation was to discover various compounds which stimulate a protein tyrosine kinase, namely fyn kinase. The N-acyl-3,5-bis(arylidene)-4-piperidones and related analogues activated this enzyme using concentrations of 25 mM while representative molecules achieved this result at 0.1 mM. Molecular modelling suggested that the compounds interact transiently with the ATP binding site of fyn kinase thereby enhancing the catalytic phosphorylation of proteins. In the future, candidate antineoplastic agents will be designed which incorporate the structural features of these enzyme stimulators with the goal of their being formed in vitro and in vivo prior to the release of cytotoxins.

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Evaluation of the thiosemicarbazones of some aryl alkyl ketones and related compounds for anticonvulsant activities

Cited by 33 publications

References 5 publications

1,5-Diaryl-3-oxo-1,4-pentadienes: A Case for Antineoplastics with Multiple Targets

1,5-Diaryl-3-oxo-1,4-pentadienes: A Case for Antineoplastics with Multiple Targets

Synthesis and cytotoxicity evaluation of thiosemicarbazones and their thiazole derivatives

N–Acyl–3,5–bis(arylidene)-4-piperidones and related compounds which stimulate fyn kinase

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