RÉSUMÉ
A highly regiospecific synthesis of a series of indenoindoles is reported, together with X-ray studies and their activity against human prostate cancer cells PC-3 and LNCaP in vitro. The most effective compound 7,7-dimethyl-5-[(3,4-dichlorophenyl)]-(4bRS,9bRS)-dihydroxy-4b,5,6,7,8,9bhexahydro-indeno[1,2-b]indole-9,10-dione 7q reduced the viability in both cell lines in a time and dose-dependent manner. Inhibitory effects were also observed on the adhesion, migration, and invasion of the prostate cancer cells as well as on clonogenic possibly by inhibition of MMP-9 activity. Molecular docking of 7q and 6k into MMP-9 human active site was also performed to determine the probable binding mode.
Sujet(s)
Antinéoplasiques/pharmacologie , Indènes/pharmacologie , Indoles/pharmacologie , Matrix metalloproteinase 9/métabolisme , Inhibiteurs de métalloprotéinases matricielles/pharmacologie , Tumeurs de la prostate/traitement médicamenteux , Tumeurs de la prostate/enzymologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/effets des médicaments et des substances chimiques , Cellules cultivées , Cristallographie aux rayons X , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Humains , Indènes/synthèse chimique , Indènes/composition chimique , Indoles/synthèse chimique , Indoles/composition chimique , Mâle , Inhibiteurs de métalloprotéinases matricielles/synthèse chimique , Inhibiteurs de métalloprotéinases matricielles/composition chimique , Simulation de docking moléculaire , Structure moléculaire , Tumeurs de la prostate/anatomopathologie , Relation structure-activitéRÉSUMÉ
This study describes the preliminary toxicity evaluation of five new furan derivatives, 2-[2-acetylamino-2-[(benzothiazolyl-substituted)aminocarbonyl]vinyl]-5-nitro furane (compounds A, B, D and E) and 2-[2-phenylamino-2-[benzothiazolylaminocarbonyl]vinyl]furane (compound C). Cytotoxicity was determined using the MTT (tetrazolium salt) method over BHK21 (Syrian baby hamster kidney) and Hep-2 (human larynx carcinoma) cells, which had previously been used to evaluate the cytotoxicity of the 5-nitrofuran derivatives. The lethal concentration 50 (LC(50)) was determined using brine shrimp (Artemia salina) bioassay. Nitrofurantoin was used as reference compound. The results demonstrate that BHK21 cells are more sensitive than Hep-2 cells. This structurally related serial of compounds shows a differential toxicity, which is an indication that the toxicity naturally arising from the nitro group can be modulated by the substituents over the furan ring. Additionally, compound C, the only derivative with no nitro group, was least toxic to Hep-2, but exhibits toxicity to BHK21 cells and brine shrimp. The LC(50 )brine shrimp test (BST) bioassay results were as follows: A, 654.2 microg ml(-1); B, 50.0 microg ml(-1); C, 533.4 microg ml(-1); D, 172.1 microg ml(-1); E, 76.4 microg ml(-1), and NF, >1000 microg ml(-1).
