1.Identification of novel nitroreductases from Bacillus cereus and their interaction with the CB1954 prodrug.
Gwenin VV1, Poornima P1, Halliwell J1, Ball P1, Robinson G1, Gwenin CD2. Biochem Pharmacol. 2015 Dec 1;98(3):392-402. doi: 10.1016/j.bcp.2015.09.013. Epub 2015 Sep 28.
Directed enzyme prodrug therapy is a form of cancer chemotherapy in which bacterial prodrug-activating enzymes, or their encoding genes, are directed to the tumour before administration of a prodrug. The prodrug can then be activated into a toxic drug at the tumour site, reducing off-target effects. The bacterial nitroreductases are a class of enzymes used in this therapeutic approach and although very promising, the low turnover rate of prodrug by the most studied nitroreductase enzyme, NfnB from Escherichia coli (NfnB_Ec), is a major limit to this technology. There is a continual search for enzymes with greater efficiency, and as part of the search for more efficient bacterial nitroreductase enzymes, two novel enzymes from Bacillus cereus (strain ATCC 14579) have been identified and shown to reduce the CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) prodrug to its respective 2'-and 4'-hydroxylamine products. Both enzymes shared features characteristic of the nitro-FMN-reductase superfamily including non-covalently associated FMN, requirement for the NAD(P)H cofactor, homodimeric, could be inhibited by Dicoumarol (3,3'-methylenebis(4-hydroxy-2H-chromen-2-one)), and displayed ping pong bi bi kinetics.
2.Anticancer effects of bishydroxycoumarin are mediated through apoptosis induction, cell migration inhibition and cell cycle arrest in human glioma cells.
Zhang CG1, Huang JC, Liu T, Li XY. J BUON. 2015 Nov-Dec;20(6):1592-600.
PURPOSE: To evaluate the cytotoxic and apoptotic effects of bishydroxycoumarin (BHC) against human glioma cells and to study their mode of action.
3.Historical hallmarks of anticoagulation and antiplatelet agents.
Tsoucalas G1, Chevallier J, Karamanou M, Papaioannou T, Sgantzos M, Androutsos G. Curr Pharm Des. 2016 Jan 11. [Epub ahead of print]
Thrombosis is a well known phenomenon among physicians since antiquity. A variety of peculiar agents, such as leeches and bark, were used to prevent it. Hirudin was used during the 19th century. The next eon, heparin, strepokinase, urokinase, TPA, dicumarol, warfarin, aspirin, ticlopidine, Clopidogrel, SSHA and SP54 provoked huge advances in anticoagulation. During 21st century with the use of fondaparinux, dabigatran, rivaroxaban and Ticagrelor antithrombotic prevention and therapeutic interaction entered an era of medical challenges. Although the risk after a thrombotic episode is now highly reduced, blood clots still present damaging or even lethal consequences in human organisms and further research is strongly recommended.
4.Naphtho[1',2':4,5]imidazo[1,2-a]pyridine-5,6-diones: Synthesis, enzymatic reduction and cytotoxic activity.
Šarlauskas J1, Pečiukaitytė-Alksnė M2, Misevičienė L2, Marozienė A2, Polmickaitė E2, Staniulytė Z2, Čėnas N2, Anusevičius Ž3. Bioorg Med Chem Lett. 2016 Jan 15;26(2):512-7. doi: 10.1016/j.bmcl.2015.11.084. Epub 2015 Nov 24.
Naphtho[1',2':4,5]imidazo[1,2-a]pyridine-5,6-diones (NPDOs), a new type of N-heterocycle-fused o-quinones, have been synthesized. They have been found to be efficient electron-accepting substrates of NADPH-dependent single-electron-transferring P-450R and two-electron transferring NQO1, generating reactive oxygen species (ROS) with a concomitant decrease in NADPH, which is consistent with redox-cycling. The reactivity of NPDOs toward P-450R (in terms of kcat/Km) varied in the range of 10(6)-10(7)M(-1)s(-1), while their reduction by NQO1 proceeded much faster, approaching the diffusion control limit (kcat/Km∼10(8)-10(9)M(-1)s(-1)). NPDOs exhibited relatively high cytotoxic activity against human lung carcinoma (A-549) and breast tumor (MCF-7) cell lines (LC50=0.1-8.3μM), while promyelocytic leukemia cells (HL-60) were less sensitive to NPDOs (LC50⩾10μM). 3-Nitro-substituted NPDO (11) revealed the highest potency against both A-549 and MCF-7 cell lines, with LC50 of 0.