ABSTRACT
The synthesis of the adamantane phenylalkylamines 2a-d, 3a-c, and 4a-e is described. These compounds exhibited significant antiproliferative activity, in vitro, against eight cancer cell lines tested. The σ(1), σ(2), and sodium channel binding affinities of compounds 2a, 3a, 4a, and 4c-e were investigated. The most interesting analogue, 4a, exhibited significant in vivo anticancer profile on pancreas, prostate, leukemia, and ovarian cancer cell line xenografts together with apoptosis and caspase-3 activation. Inhibition of the cancer cells cycle at the sub-G1 level was also obtained with 4a. Finally, encouraging results were observed with 4a in vivo on mice, suggesting putative antimetastatic and analgesic activities of this compound.
Subject(s)
Adamantane/analogs & derivatives , Adamantane/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Neuralgia/drug therapy , Piperidines/pharmacology , Receptors, sigma/metabolism , Adamantane/chemical synthesis , Adamantane/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Caspase 3/metabolism , Cell Cycle/drug effects , Female , Humans , Male , Mice , Mice, SCID , Molecular Structure , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Piperidines/chemical synthesis , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Protein Binding , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
The synthesis of N-{4-[a-(1-adamantyl)benzyl]phenyl}piperazines 2a-e is described. The in vitro antiproliferative activity of most compounds against main cancer cell lines is significant. The σ(1), σ(2)-receptors and sodium channels binding affinity of compounds 2 were investigated. One of the most active analogs, 2a, had an interesting in vivo anticancer profile against the BxPC-3 and Mia-Paca-2 pancreas cancer cell lines with caspase-3 activation, which was associated with an anagelsic activity against the neuropathic pain.
Subject(s)
Adamantane , Antineoplastic Agents , Receptors, sigma/metabolism , Adamantane/chemical synthesis , Adamantane/chemistry , Adamantane/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Inhibitory Concentration 50 , Mice , Mice, Nude , Molecular Structure , Pancreatic Neoplasms/metabolismABSTRACT
The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-adamantyl)-6,6-diarylhexylamines 3 is described and the σ1, σ2-receptors and sodium channels binding affinity of compounds 1 were investigated. The in vitro activity of compounds 1, 2 and 3 against main cancer cell lines is significant. One of the most active analogs, 1a, had an interesting in vivo anticancer profile against the ovarian cancer cell line IGROV-1, which was associated with an anagelsic activity against the neuropathic pain induced by the main anticancer drugs.
Subject(s)
Adamantane/chemistry , Adamantane/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Receptors, sigma/chemistry , Adamantane/chemical synthesis , Adamantane/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Design , Female , Humans , Male , Mice , Mice, SCID , Neoplasms/drug therapyABSTRACT
The synthesis of a number of new benzothiopyrano[4,3,2-cd]isoindole aminoderivatives designed as structural analogues of the key metabolite of the anticancer agent Ledacrine (nitracrine) and their in vitro cytotoxic activity evaluation against HCT-116, MES-SA, and MES-SA/Dx cancer cell lines is reported. The majority of the derivatives possessed noticeable cytotoxicity in a low µM range indicating an interesting structure-activity relationship.
Subject(s)
Amines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Indoles/chemical synthesis , Amines/chemical synthesis , Amines/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Indoles/chemistry , Indoles/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Nitracrine/chemistry , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrans/pharmacology , Structure-Activity Relationship , Sulfhydryl Compounds/chemical synthesis , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacologyABSTRACT
The preparation of 4-deazaformycin A has been achieved. The synthesis features the condensation of a suitably substituted, lithiated 4-picoline with 2,3,5-tri-O-benzyl-d-ribonolactone, dehydration of the resulting hemiacetal, and ionic hydrogenation, followed by manipulation of the protecting groups and subsequent ring closure with the formation of 7-amino-3-(beta-d-ribofuranosyl)pyrazolo[3,4-c]pyridine.
