Evaluation of Nuclear‐substituted Styryl Ketones and Related Compounds for Antitumor and Cytotoxic Properties

Dimmock, Jonathan R.; Taylor, Wesley G.

doi:10.1002/jps.2600640210

Cited by 40 publications

(11 citation statements)

References 29 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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“…On the other hand, the corresponding Mannich bases 7 are potent cytotoxins, some of which extended the life spans of mice with P388 leukemia but generally at doses close to causing mortalities [13]. Thus a series of conjugated styryl ketones 6 have modest cytotoxic properties and were inactive in certain in vivo anticancer screens while being well tolerated in mice.…”

Section: ) -Unsaturated Ketonesmentioning

confidence: 99%

Cytotoxic Thiol Alkylators

Pati¹,

Das²,

Sharma³

et al. 2007

MRMC

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Various classes of cytotoxic compounds which alkylate cellular thiols are described namely alpha,beta-unsaturated ketones, alpha-methylene-gamma-lactones, azines of Mannich bases, imexon, isothiocyanates, a benzoacronycine as well as activation by thiols prior to alkylation. The mechanisms of action of some of the molecules, such as the formation of reactive oxygen species, are presented. The cytotoxicity of a number of drugs can be influenced by modulation of the concentration of thiols including the observation that potencies can be increased by thiol activation. The ability of certain thiol reagents to reverse multidrug resistance as well as some miscellaneous actions of thiol alkylators are described.

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“…Thus the genotoxic properties displayed by various alkylating agents in cancer chemotherapy [3] may well be absent in conjugated enones. Initially compounds containing one α,β-unsaturated group were prepared which demonstrated cytotoxic and anticancer properties [4]. However a number of studies showed that an initial chemical insult followed by a second interaction with cellular constituents can be more harmful to tumors than nonmalignant cells [5–7].…”

Section: Introductionmentioning

confidence: 99%

Novel 3,5-bis(arylidene)-4-oxo-1-piperidinyl dimers: Structure–activity relationships and potent antileukemic and antilymphoma cytotoxicity

Santiago-Vazquez

Das

et al. 2014

European Journal of Medicinal Chemistry

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Novel clusters of 3,5-bis(benzylidene)-4-oxo-1-piperidinyl dimers 3–5 were evaluated against human Molt4/C8 and CEM T-lymphocytes and human HeLa cervix adenocarcinoma cells as well as murine L1210 leukemia neoplasms. Several of these compounds demonstrated IC50 values in the submicromolar and low micromolar range and compounds possessing 4-fluoro, 4-chloro and 3,4,5-trimethoxy substituents in the series 3 and 4 were identified as potent molecules. A heat map revealed the very high cytotoxic potencies of representative compounds against a number of additional leukemic and lymphoma cell lines and displayed greater toxicity to these cells than nonmalignant MCF10A and Hs-27 neoplasms. These dienones are more refractory to breast and prostate cancers. The evaluation of representative compounds in series 3–5 against a panel of human cancer cell lines revealed them to be potent cytotoxins with average IC50 values ranging from 0.05 to 8.51 μM In particular, the most potent compound 4g demonstrated over 382-fold and 590-fold greater average cytotoxic potencies in this screen than the reference drugs, melphalan and 5-fluorouracil, respectively. A mode of action investigation of two representative compounds 3f and 4f indicated that they induce apoptosis which is due, at least in part, to the activation of caspase-3 and depolarization of the mitochondrial membrane potential.

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Evaluation of Nuclear‐substituted Styryl Ketones and Related Compounds for Antitumor and Cytotoxic Properties

Cited by 40 publications

References 29 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

Cytotoxic Thiol Alkylators

Novel 3,5-bis(arylidene)-4-oxo-1-piperidinyl dimers: Structure–activity relationships and potent antileukemic and antilymphoma cytotoxicity

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