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 Wilms' tumour 1 (WT1) protein is over-expressed in several types of cancer including leukaemias and might therefore constitute a novel target for immunotherapy. Recently, human leucocyte antigen (HLA) class I-binding WT1 peptides have been identified and shown to stimulate CD8(+) T cells in vitro. For maximal CD8 cell efficacy, CD4(+) helper T cells responding to major histocompatibility complex (MHC) class II-binding epitopes are required. Here, we report that scanning the WT1 protein sequence using an evidence-based predictive computer algorithm (SYFPEITHI) yielded a peptide WT1(124-138) predicted to bind the HLA-DRB1*0401 molecule with high affinity. Moreover, synthetic WT1(124-138)-peptide-pulsed dendritic cells (DC), generated according to a protocol optimised in the present study, sensitised T cells in vitro to proliferate and secrete interferon-gamma (IFN-gamma) when rechallenged with specific peptide-pulsed DC, but not with peripheral blood mononuclear cells (PBMC). These results suggest that the WT1 protein may yield epitopes immunogenic to CD4 as well as CD8 T cells, and therefore constitute a novel potential target for specific immunotherapy.
