E,E,E-1-(4-Arylamino-4-oxo-2-butenoyl)-3,5-bis(arylidene)-4-piperidones: a topographical study of some novel potent cytotoxins

A series of E,E,E-3,5-bis(arylidene)-1-(4-arylamino-4-oxo-2-butenoyl)-4-piperidones 4 (phenylidene) and 5 (4-nitrophenylidene) were prepared in order to explore the structural features of the N-acyl group which affects the cytotoxic potency. Evaluation toward human Molt 4/C8 and CEM T-lymphocytes revealed that many of the IC(50) figures were submicromolar and lower than melphalan. Marked inhibitory potencies toward murine leukemia L1210 cells were also noted. When evaluated against a panel of human tumor cell lines, three representative compounds in series 4 displayed selective toxicity to leukemia and colon cancer cell lines and were significantly more potent than the reference drug melphalan. Molecular modeling of representative compounds in both series 4 and the analogs, in which the configuration of the olefinic double bond was changed from E to Z (series 3), revealed that the torsion angles of the arylidene aryl rings and locations of the terminal arylaminocarbonyl groups may have contributed to the greater cytotoxic properties displayed in 3. Compounds 4c (3,4-dichlorophenylamino), d (4-methylphenylamino) and 5c (3,4-dichlorophenylamino), d (4-methylphenylamino) inhibited the activity of human N-myristoyltransferase by approximately 50% at concentrations of 50-100 microM. The compounds in series 4 and 5 were well tolerated in a short-term toxicity study in mice.     

1-Arylmethyl-2,3-dioxo-2,3-dihydroindole thiosemicarbazones as leads for developing cytotoxins and anticonvulsants

Various substituted 1-arylmethyl-2,3-dioxo-2,3-dihydroindole thiosemicarbazones 3a-h, 1-benzyl-2,3-dioxo-2,3-dihydroindole N⁴-aryl thiosemicarbazones 4a-i and 1-benzyl-2,3-dioxy-2,3-dihydroindole N⁴-cyclohexylthiocarbazone 5 were synthesized. All of these compounds were evaluated against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 leukemia cells. Nearly 40% of these compounds possess low micromolar IC₅₀ values and some are either more potent than, or equipotent with, melphalan. Various correlations between the structures of these compounds and cytotoxic potencies were obtained which included the use of QSAR and molecular modeling techniques. Representative compounds displayed anticonvulsant properties in rats and were well tolerated by these animals. The encouraging biodata noted affords adequate rationale for outlining guidelines for further development of these molecular scaffolds.     

Molecular modifications of 2-arylidene-1-indanones leading to increased cytotoxic potencies

A series of 2-arylidene-1-indanones, 1, had been shown previously to display cytotoxic properties towards Molt 4/C8, CEM and L1210 cells. In the present study, two series of analogues of 1 were prepared namely various 2-arylidene-1,3-indandiones, 2, and chalcones, 3. In general, the potencies of compounds 2 and 3 were greater than the analogues bearing the same aryl substituents in series 1. Molecular modeling was undertaken in order to seek explanations for the variation in bioactivities.     

Cytotoxic mannich bases of 1-arylidene-2-tetralones

Various 1-arylidene-2-tetralones 1 had been shown previously to possess moderate cytotoxic properties unaccompanied by murine toxicity. The objective of the present investigation was to undertake different molecular modifications of representative members of series 1 with a view to discerning those structural features leading to increased potencies. All compounds were evaluated using human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells. The Mannich bases 2, 4, 5 and 7 possessed increased potencies compared to the corresponding unsaturated ketones 1 and in general were potent cytotoxics having IC50 values in the 0.2-10 microM range. QSAR using the cytotoxicity data for 2a-e suggested that potency was positively correlated with the size of the substituents in the arylidene aryl ring. Compounds 2a-f were evaluated using a panel of approximately 53 human tumour cell lines and, when all cell lines were considered, were more potent than the reference drug melphalan. In particular, marked antileukemic activity was displayed. Molecular modeling was utilized in order to evaluate whether the shapes of the different compounds contributed to the varying potencies observed. Representative compounds demonstrated minimal or no inhibiting properties towards human N-myristoyltransferase (NMT) and did not bind to calf thymus DNA. This study has revealed a number of unique lead molecules as candidate anti-neoplastic agents serving as prototypes for future development.     

Cytotoxic Mannich Bases of 1-Arylidene-2-tetralones

Various 1-arylidene-2-tetralones 1 had been shown previously to possess moderate cytotoxic properties unaccompanied by murine toxicity. The objective of the present investigation was to undertake different molecular modifications of representative members of series 1 with a view to discerning those structural features leading to increased potencies. All compounds were evaluated using human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells. The Mannich bases 2, 4, 5 and 7 possessed increased potencies compared to the corresponding unsaturated ketones 1 and in general were potent cytotoxics having IC50 values in the 0.2–10?μM range. QSAR using the cytotoxicity data for 2a–e suggested that potency was positively correlated with the size of the substituents in the arylidene aryl ring. Compounds 2a–f were evaluated using a panel of approximately 53 human tumour cell lines and, when all cell lines were considered, were more potent than the reference drug melphalan. In particular, marked antileukemic activity was displayed. Molecular modeling was utilized in order to evaluate whether the shapes of the different compounds contributed to the varying potencies observed. Representative compounds demonstrated minimal or no inhibiting properties towards human N-myristoyltransferase (NMT) and did not bind to calf thymus DNA. This study has revealed a number of unique lead molecules as candidate antineoplastic agents serving as prototypes for future development.     

E,E-2-Benzylidene-6-(nitrobenzylidene)cyclohexanones: syntheses, cytotoxicity and an examination of some of their electronic, steric, and hydrophobic properties

Three series of structurally isomeric 2-benzylidene-6-(nitrobenzylidene) cyclohexanones 1-3 were prepared and evaluated against human Molt/C8 and CEM T-lymphocytes as well as murine L1210 cells. The IC(50) values of the majority of compounds are less than 10microM and in some assays, the figures for 1d and 1e are submicromolar. Correlations were discerned between cytotoxic potencies and the atomic charges on one of the olefinic carbon atoms, the torsion angles between an aryl ring, and the adjacent unsaturated group as well as logP values. Three representative compounds were examined for their effect on respiration in rat liver mitochondria.     

Tumour-specific cytotoxicity and structure–activity relationships of novel 1-[3-(2-methoxyethylthio)propionyl]-3,5-bis(benzylidene)-4-piperidones

A series of 1-acyl-3,5-bis(benzylidene)-4-piperidones 3–7 were designed and synthesized as novel cytotoxic agents. These compounds displayed potent cytotoxic properties towards human Molt4/C8, CEM, HSC-2, HSC-3 and HSC-4 neoplasms and also to murine L1210 cells. The majority of the compounds have sub-micromolar or very low micromolar IC₅₀ and CC₅₀ values and are significantly more potent than the reference alkylating drug melphalan. Evaluation of these compounds against non-malignant HGF and HPLF cells revealed the tumour-specific toxicity. In particular, 3e emerged as a promising lead cytotoxic agent which caused apoptosis and PARP1 cleavage in HSC-2 cells.     

Synthesis,antineoplastic and cytotoxic activities of some mononuclear Ru(II) complexes

A series of mononuclear Ru(II) complexes of the type [Ru(S)₂(K)]²⁺, where S = 1,10-phenanthroline/2,2′-bipyridine and K = 4-OH-btsz, 4-CH₃-btsz, 3,4-di-OCH₃-btsz, 4-OH-binh, 4-CH₃-binh, 3,4-di-OCH₃-binh, were prepared and characterized by elemental analysis, FTIR, ¹H-NMR, and mass spectroscopy. The complexes displayed metal–ligand charge transfer (MLCT) transitions in the visible region. These ligands formed bidentate octahedral ruthenium complexes. The title complexes were evaluated for their in vivo anticancer activity against a transplantable murine tumor cell line, Ehrlisch’s ascites carcinoma (EAC), and in vitro cytotoxic activity against human cancer cell lines Molt 4/C₈ and CEM and murine tumor cell line L1210. The ruthenium complexes showed promising biological activity especially in decreasing tumor volume and viable ascites cell counts. Treatment with these complexes prolonged the life span of mice bearing EAC tumors by 10–52%. In vitro evaluation of these ruthenium complexes revealed cytotoxic activity from 0.21 to 24 μM against Molt 4/C₈, 0.16 to 19 μM aginst CEM, and 0.75 to 32 μM against L1210.     

Synthesis, anticancer, and cytotoxic activities of some mononuclear Ru(II) compounds

The synthesis and characterization of ruthenium compounds (Ru1-Ru12) of the type [Ru(S)(2)(K)], (where S=1,10-phenanthroline/2,2'-bipyridine and K=itsz, MeO-btsz, 4-Cl-btsz, 2-Cl-btsz, 2-F-btsz, hfc and itsz=isatin-3-thiosemicarbazone, MeO-btsz=1-(4'-methoxy-benzyl)-thiosemicarbazone, hfc=2-{[3-chloro-4-fluoro-phenylimino]methyl}phenol, 4-Cl-btsz=1-(4'-chlorobenzyl)-thiosemicarbazone, 2-Cl-btsz=1-(2'-chloro benzyl)-thiosemicarbazone, 2-F-btsz=1-(2'-fluorobenzyl)-thiosemicarbazone) are described. These ligands form bidentate octahedral ruthenium compounds. The title compounds were subjected to in vivo anticancer activity against a transplantable murine tumor cell line Ehrlich's Ascites Carcinoma (EAC) and in vitro cytotoxic activity against human cancer cell line Molt 4/C8, CEM and murine tumor cell line L1210. Ruthenium compounds (Ru1-Ru12) showed promising biological activity especially in decreasing tumor volume and viable ascites cell counts. Treatment with these compounds prolonged the life span of mice bearing EAC tumor by 10-43%. In vitro evaluation of these ruthenium compounds revealed cytotoxic activity from 0.24 to 27 microM against Molt 4/C8, 0.27 to 48 microM against CEM, and 0.94 to 248 microM against L1210. Their ligands alone failed to show cytotoxic activity at the concentrations tested (68-405 microM).     

1-Arylmethyl-2,3-dioxo-2,3-dihydroindole thiosemicarbazones as leads for developing cytotoxins and anticonvulsants

Various substituted 1-arylmethyl-2,3-dioxo-2,3-dihydroindole thiosemicarbazones 3a-h, 1-benzyl-2,3-dioxo-2,3-dihydroindole N(4)-aryl thiosemicarbazones 4a-i and 1-benzyl-2,3-dioxy-2,3-dihydroindole N(4)-cyclohexylthiocarbazone 5 were synthesized. All of these compounds were evaluated against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 leukemia cells. Nearly 40% of these compounds possess low micromolar IC(50) values and some are either more potent than, or equipotent with, melphalan. Various correlations between the structures of these compounds and cytotoxic potencies were obtained which included the use of QSAR and molecular modeling techniques. Representative compounds displayed anticonvulsant properties in rats and were well tolerated by these animals. The encouraging biodata noted affords adequate rationale for outlining guidelines for further development of these molecular scaffolds.     

Synthesis of a series of fully methylated aldobiouronic acids,and β-elimination reactions of their synthetic precursors

Treatment of methyl 2,3,4-tri-O-acetyl-l-bromo-l-deoxy-α-d-glucopyranuronate severally with 2,4,6-, 2,3,6-, and 2,3,4-tri-O-methyl derivatives of methyl α-d-glucopyranoside and with methyl 4,6-O-benzylidene-3-O-methyl-α-d-glucopyranoside, in the presence of silver carbonate, afforded crystalline aldobiouronic acid derivatives in high yield. Deacetylation followed by methylation gave a series of fully methylated derivatives of laminaribiouronic, cellobiouronic, and gentiobiouronic acids, and the (1 → 2)-linked analogue. Methylation with methyl iodide and silver oxide in N,N-dimethylformamide was invariably accompanied by a small amount ofβ-elimination, with the formation of olefinic disaccharides which were also obtained by β-elimination reactions of the precursor acetates followed by methylation. Methyl 4,5-unsaturated 4-deoxyhexopyranosyluronate derivatives were the main products of the reaction, but these underwent further degradation with cleavage of the interglycosidic linkage and formation of 6-methoxycarbonyl-4-pyrone.     

Synthesis of novel branched-chain amino sugars: methyl l-sibirosaminide and N-acylkansosamine

Methyl l-sibirosaminide and N-acylkansosamine were synthesized via the same intermediate, methyl 4-amino-4,6-dideoxy-2,3-O-isopropylidene-3-C-methyl-α-l-mannopyranoside (7), from l-rhamnose in 7 and 10 steps, respectively. Conversion of 7 into the title compounds was performed by N-methylation or N-(2-methoxypropanoyl)ation followed by appropriate derivatization.     

Niacin esters of chalcones with tumor-selective properties

Novel series of niacin esters of chalcones 2, 4 and 6 were designed as antineoplastic agents that have the potential to release the chemoprotectant niacin. These enones are cytotoxic to human CD₄^+?T-lymphocyte Molt 4/C8 and CEM and murine leukemia L1210 cells. Quantitative structure–activity relationship (QSAR) studies of the biodata in series 4 revealed that cytotoxic potency was enhanced by placing electron-repelling groups in one of the aryl rings. The compounds are lethal to HL-60, HSC-2, HSC-3 and HSC-4 neoplasms but less toxic to nonmalignant hepatocyte growth factor, hematopoietic progenitor cell and human periodontal ligament fibroblast cells. Hence, the compounds display tumor-selective toxicity. These chalcones are well tolerated in mice and no overt toxicity was noted. The results establish that in general the compounds in series 2, 4 and 6 have positive characteristics which warrant further studies.     

1-Naphthyl and 4-indolyl arylalkylamines as selective monoamine reuptake inhibitors

A series of enantiomerically pure 1-naphthyl and 4-indolyl arylalkylamines were prepared and evaluated for their binding affinities to the monoamine transporters. The two series of enantiomers displayed considerable differences in binding selectivity between the monoamine transporters, leading to the design of (S)-4-(3,4-dichlorophenyl)-4-(1H-indol-4-yl)-N-methylbutan-1-amine as a potent inhibitor for the dopamine and serotonin transporters.     

Synthetic approaches to 6-substituted 9-(3-azido-3,4-dideoxy-β-d,l-erythro-pentopyranosyl)purines

Methyl 3-azido-2-O-benzoyl-3,4-dideoxy-β-dl-erythro-pentopyranoside (6) was synthesized through two routes in five steps from methyl 2,3-anhydro-4-deoxy-β-dl-erythro-pentopyranoside (1). The first route proceeded via selective azide displacement of the 3-tosyloxy group of methyl 4-deoxy-2,3-di-O-tosyl-α-dl-threo-pentopyranoside, followed by detosylation and benzoylation. The second route consisted, with a better overall yield, in the azide displacement of the mesyloxy group of methyl O-benzoyl-4-deoxy-3-O-methylsulfonyl-α-dl-threo-pentopyranoside (10), obtained by benzylate opening of 1, followed by benzoylation, debenzylation, and mesylation. Compound 6 was transformed into its glycosyl chloride, further treated by 6-chloropurine to give the nucleoside 9-(3-azido-2-O-benzoyl-3,4-dideoxy-β-dl-erythro-pentopyranosyl)-6-chloropurine (13). When treated with propanolic ammonia, 13 yielded 9-(3-azido-3,4-dideoxy-β-dl-erythro-pentopyranosyl)adenine.     

Synthesis and antimicrobial activity of some new substituted pyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidinone derivatives

A series of new 3-substituted-7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,4-dichlorophenyl)-2-methylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one derivatives were synthesized as antimicrobial agents using 7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,4-dichlorophenyl)-2-methyl-4H-pyrido[3′,2′:4,5]thieno[3,2-d]-[1,3]oxazin-4-one as a starting compound. Its condensation with substituted aniline derivatives or phenyl hydrazine gave the corresponding N-substituted derivatives. Treatment of the starting compound with hydrazine hydrate afforded the corresponding N-amino derivative, which was reacted with substituted phenylisocyanate and phenylisothiocyanate derivatives to give the corresponding semicarbazides and thiosemicarbazide derivatives. All the newly synthesized compounds were evaluated for their antimicrobial activities in comparison to streptomycin and fusidic acid as positive controls. The structure assignments of the new compounds are based on chemical and spectroscopic evidence.     

Metalloporphyrin catalyzed oxidation of methyl yellow and related azo compounds

Fe(TDCPP)Cl catalyzes the oxidation of simple azo compounds including 4-phenylazoaniline, 4-(phenylazo)-N-methylaniline and 4-(phenylazo)-N,N-dimethylaniline (methyl yellow). Methyl yellow and 4-(phenylazo)-N-methylaniline are N-demethylated to form 4-phenylazoaniline prior to further oxidation. Oxidation of 4-phenylazoaniline generates a variety of products as a result of multiple reaction pathways occurring simultaneously. One pathway for the oxidation of 4-phenylazoaniline involves oxidative cleavage of the azo linkage while additional pathways result in modification of 4-phenylazoaniline without cleavage of the azo linkage. One of these additional reaction pathways includes the formation of an additional azo linkage to yield 1,4′-bis(phenylazo)azobenzene.     

Synthesis and bradykinin inhibitory activity of novel non-peptide compounds,and evaluation of in vivo analgesic activity

A series of novel non-peptide diamide compounds was synthesized and evaluated as antibradykinin agents by utilizing guinea-pig ileum smooth muscle. Among the final compounds, (Z)-4-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-4-oxo-N-(4-phenylbutan-2-yl)but-2-enamide showed most favorable bradykinin inhibitory activity and demonstrated analgesic efficacies in the rat models of inflammatory and neuropathic pain.     

Small-molecular inhibitors of Ca2+-induced mitochondrial permeability transition (MPT) derived from muscle relaxant dantrolene

A structure consisting of substituted hydantoin linked to a 5-(halophenyl)furan-2-yl group via an amide bond was identified as a promising scaffold for development of low-molecular-weight therapeutic agents to treat vascular dysfunction, including ischemia/reperfusion injury. Among the compounds synthesized, 5-(3,5-dichlorophenyl)-N-{2,4-dioxo-3-[(pyridin-3-yl)methyl]imidazolidin-1-yl}-2-furamide (17) possessed the most potent inhibitory activity against Ca²⁺-induced mitochondrial swelling. The structural development, synthesis and structure–activity relationship of these compounds are described.     

Synthesis,Antiproliferative, and Antiviral Evaluation of Certain Acyclic 6-Substituted Pyrrolo[2,3-D]-pyrimidine Nucleoside Analogs Related to Sangivamycin and Toyocamycin

Abstract

A number of 6-substituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine and 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidine derivatives related to the nucleoside antibiotics toyocamycin and sangivamycin were prepared and tested for their biological activity. Treatment of 2-amino-5-bromo-3,4-dicyanopyrrole (2) with triethylorthoformate, followed by alkylation via the sodium salt method with either 2-(acetoxyethoxy)methyl bromide or (1,3-diacetoxy-2-propoxy)methyl bromide, furnished the corresponding N-substituted pyrroles 3a and 3b. These compounds were then smoothly converted to the requisite deprotected 4-amino-6-bromopyrrolo[2,3-d]-pyrimidine-5-carbonitriles 5a and 5b (toyocamycin analogs) by methanolic ammonia. The 6-amino-derivatives were obtained by a displacement of the bromo group with liquid ammonia. Conventional functional group transformations involving the 5-cyano group furnished the 5-carboxamide (sangivamycin) and 5-thioamide analogs. Compounds substituted at the 7-position with a ribosyl moiety were active against human cytomegalovirus (HCMV) at micromolar concentrations, but the apparent activity was not selective. The 7-ribosyl compounds also had no activity against human immunodeficiency virus (HIV), though they were all cytotoxic. The new compounds were also evaluated against HCMV, herpes simplex virus type I (HSV-1), HIV, and also for their ability to inhibit the growth of L1210 murine leukemic cells in vitro. None of these compounds with (2-hydroxyethoxy)methyl substituents or 7-(1,3-dihydroxy-2-propoxy)methyl substituent at N-7 showed significant cytotoxicity toward L1210, or toward uninfected human foreskin fibroblasts (HFF cells), and KB cells. Nor were they cytotoxic in human lines CEM or MT2. Only compound 4a was found to be active against HCMV, having an IC₅₀ of 32 μM.