RESUMEN
A series of 3,5-bis(arylidene)-4-piperidones 1 and related N-acryloyl analogues 2 were prepared as candidate cytotoxic agents with a view to discerning those structural features which contributed to bioactivity. A number of the compounds were markedly cytotoxic toward murine P388 and L1210 leukemic cells and also to human Molt 4/C8 and CEM neoplasms. Approximately 40% of the IC50 values generated were lower than the figures obtained for melphalan. In virtually all cases, the N-acyl compounds were significantly more bioactive than the analogues 1. In general, structure-activity relationships revealed that the cytotoxicity of series 1 was correlated positively with the size of the aryl substituents, while in series 2, a -sigma relationship was established. In particular, various angles and interatomic distances were obtained by molecular modeling, and the presence of an acryloyl group on the piperidyl nitrogen atom in series 2 affected the relative locations of the two aryl rings. This observation, along with some differences in distances between various atoms in series 1 and 2, may have contributed to the disparity in cytotoxicity between 1 and 2. The results obtained by X-ray crystallography of representative compounds were mainly in accordance with the observations noted by molecular modeling. Selected compounds interfered with the biosynthesis of DNA, RNA, and protein in murine L1210 cells, while others were shown to cause apoptosis in the human Jurkat leukemic cell line. This study has revealed the potential of these molecules for development as cytotoxic and anticancer agents.
Asunto(s)
Acrilatos/síntesis química , Antineoplásicos/síntesis química , Piperidinas/síntesis química , Acrilatos/química , Acrilatos/farmacología , Animales , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Aspergillus fumigatus/efectos de los fármacos , Candida albicans/efectos de los fármacos , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Modelos Moleculares , Oxidación-Reducción , Piperidinas/química , Piperidinas/farmacología , ARN/antagonistas & inhibidores , ARN/biosíntesis , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Five series of novel compounds were synthesized in order to evaluate the theory of sequential cytotoxicity which seeks to exploit the view that various cancer cells are particularly susceptible to successive attacks by cytotoxic agents. The compounds prepared were various 2-[4-(3-aryl-2-propenoyloxy)phenylmethylene]cyclohexanone s 1 and the related Mannich bases 2. In addition the analogues 3-5 lacking an olefinic bond in the ester group were also synthesized, which were predicted to be less cytotoxic than the compounds of series 1 and 2. The atomic charges at the potential sites for interaction with cellular constituents were determined by molecular modeling calculations. The biodata obtained from murine and human neoplastic cells revealed that the predictions made regarding the viability of the theory were fulfilled in approximately two-thirds of the cases indicating that further investigation of this hypothesis is warranted. In addition, the significant potencies of some of the Mannich bases toward human tumor cell lines, in particular coupled to their selective toxicity toward human leukemic and colon cancer cells, confirms their usefulness in serving as lead molecules for further development. A preliminary investigation into the mode of action of representative compounds revealed their ability to induce apoptosis and inhibit the biosyntheses of ribonucleic acid and proteins.
Asunto(s)
Antineoplásicos/síntesis química , Ciclohexanonas/síntesis química , Bases de Mannich/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Cristalografía por Rayos X , Ciclohexanonas/química , Ciclohexanonas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Bases de Mannich/química , Bases de Mannich/farmacología , Ratones , Modelos Moleculares , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/biosíntesis , ARN Neoplásico/antagonistas & inhibidores , ARN Neoplásico/biosíntesis , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A number of 2-arylidenecyclohexanones 1, 2, 6-bis(arylidene)cyclohexanones 2 and related Mannich bases 3-5 were prepared. Various torsion angles as well as atomic charges on olefinic carbon atoms were determined by molecular modelling on all compounds. These molecules showed cytotoxicity towards murine P388 and L1210 cells as well as to human Molt 4/C8 and CEM T-lymphocytes. The average cytotoxicity of the dienones 2 was more than three times greater than was found with the monoarylidene analogues 1, and, in general, were slightly more cytotoxic than the Mannich bases 3-5. A number of the compounds displayed potency towards a panel of human tumour cell lines and most of the representative compounds in series 2-5 were selectively toxic to colon cancers and leukaemic cells.
Asunto(s)
Antineoplásicos/farmacología , Ciclohexanonas/farmacología , Animales , Antineoplásicos/química , Cristalografía por Rayos X , Ciclohexanonas/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Estructura Molecular , Células Tumorales CultivadasRESUMEN
Various 2-arylideneindanones 1, 2-arylidenetetralones 2, and 2-arylidenebenzosuberones 3 were synthesized with the aim of determining the relative orientations of the two aryl rings which favored cytotoxicity. Molecular modeling of the unsubstituted compound in each series revealed differences in the spatial arrangements of the two aryl rings, and evaluation of these compounds against P388, L1210, Molt 4/C8, and CEM cells as well as a panel of human tumor cell lines indicated that in general the order of cytotoxicity was 3 > 2 > 1. In particular 2-(4-methoxyphenylmethylene)-1-benzosuberone (3k) had the greatest cytotoxicity, possessing 11 times the potency of the reference drug melphalan when all five screens were considered. Series 3 was considered in further detail. First, excision of the aryl ring fused to the cycloheptanone moiety in series 3 led to some 2-arylidene-1-cycloheptanones 4 which had approximately one-third of the bioactivity of the analogues 3. Second, in some screens cytotoxicity was correlated negatively with the sigma values and positively with the MR constants of the substituents in the arylidene aryl ring of 3. Third, X-ray crystallography of five representative compounds (3i,k-n) revealed differences in the locations of the aryl rings which may have contributed to the variations in cytotoxicity. Finally three members of series 3 inhibited RNA and protein syntheses and induced apoptosis in human Jurkat T cells. This study has revealed that 2-arylidene-1-benzosuberones are a group of useful cytotoxic agents, and in particular 3k serves as a prototypic molecule for subsequent structural modifications.