Novel classes of dimer antitumour drug candidates.
Polyvalency in the biological world is defined as the simultaneous binding of multiple ligands to one receptor. Polyvalency can increase the affinity of the polyvalent ligand by 100-1000 fold over the monovalent ligand. Such phenomenon has been employed to design polyvalent toxin inhibitors. Bivalency is a similar approach where two ligands are joined together with a linker to form a homo- or hetero-dimer with an increase in affinity by up to several hundred fold over the monovalent ligand. This review will summarize the recent advancement in designing bivalent inhibitors to be used as antitumour agents. Some dimers (e.g. artemisinin homo-dimer) simply increase the affinity of the monovalent ligands without detailed knowledge of the target. Other dimers are designed with well-characterized targets, for example, jesterone dimer (inhibiting Rel/NF-kappaB) and 3,3'-diindolymethane and their derivatives (inhibiting Akt and NFkappaB). Some dimers are designed based on the high definition structure between ligand and target (e.g. benzodiazepine and daunorubicin interacting with DNA). Heterodimers have also been produced by combining either two different antitumor drugs (e.g. cis-platin/acridine or cis-platin/naphthalimide) or combining one antitumor candidate (artemisinin) with a molecule which can increase the efficacy of the former (transferrin receptor). Finally we will discuss the design of bivalent inhibitors of the P-glycoprotein (ABCB1; MDR or P-gp) to overcome the problem of antitumor resistance.
Chow
Larry M C
LM
Department of Applied Biology and Chemical Technology and Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong Polytechnic University, Hong Kong SAR. bclchow@polyu.edu.hk
Chan
Tak Hang
TH
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D011485:Protein Binding
D000970:Antineoplastic Agents; D008024:Ligands