Design and synthesis of diazepine inhibitors as novel anti-cancer agents.

Doctoral thesis English OPEN
Hamidi, Parinaz.
  • Subject: RM
    mesheuropmc: biological phenomena, cell phenomena, and immunity | enzymes and coenzymes (carbohydrates)

Cancer is a new growth that arises from abnormal and uncontrolled division of cells that may go on to invade and destroy surrounding tissues. The eukaryotic cell cycle consists of a complex sequence of events that regulates cell division and responses to DNA damage. These processes rely upon several key enzymes, including the cyclin dependent kinases (CDKs), checkpoint kinases (Chk2) and poly(ADP-ribose)polymerase-l (PARP-1). CDKs are a family of protein kinases that control progression of the cell cycle, and are themselves regulated by a complex network of activating and inhibitory mechanisms. The vital importance of CDKs in regulating of the cell cycle, emphasise their importance as anti-cancer drug targets. CDKs inhibitors compete with the natural substrate ATP in a competitive manner. Hymenialdisine and kenpaullone have been identified as novel and potent CDK inhibitors both containing an unusual azepinone scaffold. Checkpoint kinase 2 (Chk2) is a novel target for anti-cancer drug design. The enzyme mediates cell proliferation in response to DNA damage by inducing cell cycle arrest, which facilitates the DNA repair pathways. Chk2 inhibition has been recognised as a potential target for the chemopotentiation of current anti-cancer treatments. Few Chk2 inhibitors are known, kenpaullone has been identified as a novel and selective ATP competitive Chk2 inhibitor (IC50 = 0.8 uM). Debromohymenialdisine (DBH) also containing an azepinone scaffold has also been reported to inhibit Chk2. Poly(ADP-ribose)polymerase-l (PARP-1) is activated in response to DNA damage, and inhibition can potentiate cancer chemotherapy and radiotherapy. A PARP-1 inhibitor in combination with a cytotoxic agent should enhance drug activity by blocking the repair capabilities of PARP-1 in cancer cells. Although many types of inhibitors have been identified for each of these three enzymes, compounds containing a seven-membered lactam ring have been identified as key inhibitors for CDKs/Chk2/PARP-l. This study is entered upon developing the synthesis for a series of novel inhibitors of these three enzymes containing the essential lactam pharmacophore in their structures. The compounds synthesised in this study were assessed by a number of biological assays showing moderate or good growth or catalytic inhibitory activity against CDKs and PARP-1 respectively, while assays against Chk2 showed no inhibition.
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    2cpk Protein Data Bank
    2phk Protein Data Bank
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