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• W1483496550 abstract "Platinum(IV) complexes are usually inert and stable compounds which can bephotoactive pro-drugs to produce Pt(II) species with promising anti-canceractivity. Studies of the photochemistry of Pt(IV) complexes by time-dependentdensity functional theory (TDDFT) and spectroscopic methods show closeagreement. Broad exploration of cis/trans geometries, trans influences, the natureof the OR− and (pseudo)halogen ligands, electron-withdrawing/donating/delocalizing substituents on the N-ligands, and intramolecular H-bonds shows that(1) the design of platinum(IV) complexes with intense bands shifted towardslonger wavelengths (~330 nm) can be achieved by introducing intramolecular Hbondsinvolving the OH ligands and 2-hydroxyquinoline or by iodido ligands, (2)mesomeric electron-withdrawing substituents on pyridine result in low-energyabsorption with significant intensity in the visible region, and (3) the distinctmakeup of the molecular orbitals in electronic transitions for cis/trans-{Pt(N3)2}isomers result in different photoproducts. In general, the comparison of theoptimised geometries shows that Pt(IV) complexes with longer Pt−L bonds aremore likely to undergo photoreduction with longer-wavelength light. Complextrans, trans, trans-[Pt(N3)2(OH)2(NH3)(4-nitropyridine)] was first synthesised.The experimental UV-Vis spectrum in aqueous solution correlates well with theintense band in the computed spectrum whereas the overlay in the low-energyabsorption region can be improved by a solvent model. This combinedcomputational and experimental study shows that TDDFT can be a design tool totune the coordination environment for optimizing photoactive Pt(IV) compoundsas anticancer agents without immediate need for synthesis. Additionally, molecular modeling is used to study DNA distortions induced bybinding metal-containing fragments derived from cisdiamminodichloroplatinum(II) (cisplatin) and a new class of photoactive platinumanticancer drugs. Ligand field molecular mechanics (LFMM) parameters for Pt–guanine interactions are derived and validated against a range of experimentalstructures from the Cambridge Structural Database, published quantummechanics/molecular mechanics (QM/MM) structures of model Pt-DNA systemsand additional DFT studies. LFMM gives a good description of the local Ptguaninecoordination at a fraction of the computational cost of QM/MM methods.The force field is then used to develop protocols for ligand field moleculardynamics (LFMD) simulations using experimentally characterised bifunctionalDNA adducts involving both an intra- and an interstrand crosslink of cisplatin as aprelude to studying the interaction of trans-{Pt(py)2}2+ (P, py = pyridine), themajor photoproduct of the novel platinum(IV) complex trans,trans,trans-[Pt(N3)2(OH)2(py)2] (17), with the DNA duplex dodecamer,d(C1C2T3C4T5C6G7T8C9T10C11C12)• d(G13G14A15G16A17C18G19A20G21A22G23G24).Based on the observed formation of a trans species when 17 is photoreduced inthe presence of 5’-guanosine monophosphate plus the major-groove binding modeof the monofunctional complex cis-{Pt(NH3)2(py)}2+, P is proposed to coordinateto G7 and G19. This P-DNA adduct has a widened minor groove at one end of theplatinated site and deepened minor groove at the opposite end, and exhibits aglobal bend of ~67° and an unwinding of ~20°. Brabec et al. subsequentlydemonstrated experimentally that such interstrand GG crosslinks can form as aresult of the photoactivation of 17 in the presence of DNA. Such cross-links offer possibilities for specific protein–DNA interactions and suggest possiblemechanisms to explain the high potency of this photoactivated complex." @default.
• W1483496550 created "2016-06-24" @default.
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• W1483496550 date "2011-10-01" @default.
• W1483496550 modified "2023-09-24" @default.
• W1483496550 title "Computer-aided drug design of photoactivated platinum anticancer complexes" @default.
• W1483496550 hasPublicationYear "2011" @default.
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