ABSTRACT
Synthesis of mixed imine-amine pyrrolobenzodiazepine (PBD) dimers that are comprised of DC-81 and secondary amine (N10) of DC-81 subunits tethered to their C8 positions through alkanedioxy linkers (comprised of three and five carbons) is described. These noncross-linking unsymmetrical molecules exhibit significant DNA minor groove binding ability and one of them 5b linked through the pentanedioxy chain exhibits efficient DNA binding ability (DeltaTm=11.0 degrees C) when compared to naturally occurring DC-81, 1 (DeltaTm=0.7 degrees C). The imine-amine PBD dimers exhibit promising in vitro antitumor activity in a number of human cancer cell lines.
Subject(s)
Amines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Benzodiazepines/chemical synthesis , Benzodiazepines/toxicity , Imines/chemistry , Intercalating Agents/chemical synthesis , Intercalating Agents/toxicity , Pyrroles/chemical synthesis , Pyrroles/toxicity , Amines/chemical synthesis , Amines/toxicity , Antineoplastic Agents/metabolism , Base Sequence , Benzodiazepines/metabolism , Cell Line, Tumor , DNA/metabolism , Dimerization , Drug Design , Humans , Imines/chemical synthesis , Imines/toxicity , Intercalating Agents/metabolism , Models, Molecular , Molecular Sequence Data , Pyrroles/metabolismABSTRACT
Two moieties of epipodophyllotoxin have been linked at C4-position to provide novel bisepipodophyllotoxin analogues. These have been evaluated for their anticancer potential and DNA-topoisomerase II poisoning activity. Most of these analogues have exhibited promising in vitro anticancer activity against different human tumour cell lines and interestingly 4(')-O-methylated analogues have shown increased cytotoxic activity. Similarly, the DNA-topo II poisoning activity tested for these compounds has not only exhibited the DNA cleavage potential comparable to etoposide, but for some compounds this cleavage potential is superior to etoposide. Further, an interesting structure-activity relationship of these epipodophyllotoxin dimers have been generated on the basis of GI(50) values. The equations indicated that GI(50) activity is strongly dependent on structural and thermodynamic properties. These QSAR results are discussed in conjunction with conformational analysis from molecular modelling studies. QSAR models developed in these studies will be helpful in the future to design novel potent bispodophyllotoxin analogues by minor structural modifications.
Subject(s)
Podophyllotoxin , Quantitative Structure-Activity Relationship , Cell Division/drug effects , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , Podophyllotoxin/analogs & derivatives , Podophyllotoxin/chemical synthesis , Podophyllotoxin/pharmacology , Topoisomerase II InhibitorsABSTRACT
Celecoxib, a specific inhibitor of cycloxygenase-2 (COX-2) is a poorly water-soluble nonsteroidal anti-inflammatory drug with relatively low bioavailability. The effect of beta-cyclodextrin on the aqueous solubility and dissolution rate of celecoxib was investigated. The possibility of molecular arrangement of inclusion complexes of celecoxib and beta-cyclodextrin were studied using molecular modeling and structural designing. The results offer a better correlation in terms of orientation of celecoxib inside the cyclodextrin cavity. Phase-solubility profile indicated that the solubility of celecoxib was significantly increased in the presence of beta-cyclodextrin and was classified as A(L)-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by freeze drying, evaporation, and kneading methods were characterized using differential scanning calorimetry, powder x-ray diffractometry, and scanning electron microscopy. In vitro studies showed that the solubility and dissolution rate of celecoxib were significantly improved by complexation with beta-cyclodextrin with respect to the drug alone. In contrast, freeze-dried complexes showed higher dissolution rate than the other complexes.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cyclodextrins/chemistry , Sulfonamides/chemistry , beta-Cyclodextrins , Calorimetry, Differential Scanning , Celecoxib , Microscopy, Electron, Scanning , Models, Molecular , Powders/chemistry , Protein Conformation , Pyrazoles , Solubility , X-Ray DiffractionABSTRACT
Chrysene-linked pyrrolobenzodiazepine hybrids have been prepared that possess cytotoxicity in some cancer cell lines. They also exhibit promising DNA-binding affinity and this is supported by molecular modeling studies.
