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EVALUATION OF SOME ALPHA- AND BETA- AMINO DERIVATIVES OF CONJUGATED STYRYL KETONES AS ANTINEOPLASTIC AGENTS

Date

1987

Journal Title

Journal ISSN

Volume Title

Publisher

ORCID

Type

Degree Level

Doctoral

Abstract

α, ß-Unsaturated ketones and related derivatives are known to possess alkylating potential which has been associated with their biological properties. Therefore, this group of compounds can be classified as biological alkylators and hence fall in the category of the well known clinically useful anticancer drugs generally referred to as the alkylating agents. The objectives of the present investigation can be outlined briefly as follows. 1) The design, synthesis and antineoplastic evaluation tin vivo (by the NCI) and in vitro studies] of potential antineoplastic agents which are derivatives of conjugated styryl ketones. These includes the α'-bromo, the α'- and ß'-amino deriva-tives and related compounds. 2) To investigate the chemical reactivity of the compounds towards a model biological nucleophile (glutathione) and to seek correlation with biological activity. 3) To determine two further physicochemical parameters (the ionization constants and apparent partition coefficients) and to correlate these parameters with any observable anticancer activity. Earlier work from the laboratories of Dr. J.R. Dimmock have shown that the conjugated styryl ketones E(12), 1-aryl-1-nonen-3-ones] are virtually nontoxic to mice and lack in vivo activity against the P388 and L1210 murine leukemias. However, the corresponding Mannich bases (15) demonstrated significant cytotoxicity and murine toxicity. Based on the results obtained from the kinetic data, it was suggested that the disparity in both bioactivity and chemical reactivity between the styryl ketones and the corresponding Mannich bases could be due in part to the operating polar effects (inductive and/or field effects) in the latter since the Mannich bases were found to react approximately 240 times faster than the corresponding ketones . In order to investigate further if these effects are solely responsible for the differences stated above, compounds in series III (n=0, 1), where the distance between the carbonyl carbon and the quadrivalent nitrogen was varied were prepared and screened against the P388 lymphocytic leukemia in mice. All the compounds in this series were void of activity and were generally not murine toxic. The second order rate constants for the addition reaction of the compounds with glutathione were measured in formate buffer pH 4.50 at 37°C. No correlation could be discerned between the biological activity in vivo and chemical reactivities of the mono-Mannich bases (III, n=1) and the nor-derivatives (III, n=0) although the' nor compounds were found to be approximately 5 times more reactive towards glutathione than the corresponding Mannich derivatives. This difference in chemical reactivity has been attributed to be mainly due to the operating field effect (e----d9 interaction) due to the presence of the geminal dimethyl groups which imposes restriction to rotation on the onium group. The contribution from the inductive effect has been reasoned to be negligible in this series of compounds because the $-carbon is distally placed to the onium group. This is because each atom involved in the inductive effect will attenuate the electro-nic effect; hence this effect will decrease with distance.

Description

Keywords

Mannich bases

Citation

Degree

Doctor of Philosophy (Ph.D.)

Department

Pharmacy

Program

Advisor

Committee

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DOI

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