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Computer-aided drug design of photoactivated platinum anticancer complexes
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Tai, Hui-Chung (2011) Computer-aided drug design of photoactivated platinum anticancer complexes. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b2669617~S1
Abstract
Platinum(IV) complexes are usually inert and stable compounds which can be
photoactive pro-drugs to produce Pt(II) species with promising anti-cancer
activity. Studies of the photochemistry of Pt(IV) complexes by time-dependent
density functional theory (TDDFT) and spectroscopic methods show close
agreement. Broad exploration of cis/trans geometries, trans influences, the nature
of 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 towards
longer wavelengths (~330 nm) can be achieved by introducing intramolecular Hbonds
involving the OH ligands and 2-hydroxyquinoline or by iodido ligands, (2)
mesomeric electron-withdrawing substituents on pyridine result in low-energy
absorption with significant intensity in the visible region, and (3) the distinct
makeup of the molecular orbitals in electronic transitions for cis/trans-{Pt(N3)2}
isomers result in different photoproducts. In general, the comparison of the
optimised geometries shows that Pt(IV) complexes with longer Pt−L bonds are
more likely to undergo photoreduction with longer-wavelength light. Complex
trans, trans, trans-[Pt(N3)2(OH)2(NH3)(4-nitropyridine)] was first synthesised.
The experimental UV-Vis spectrum in aqueous solution correlates well with the
intense band in the computed spectrum whereas the overlay in the low-energy
absorption region can be improved by a solvent model. This combined
computational and experimental study shows that TDDFT can be a design tool to
tune the coordination environment for optimizing photoactive Pt(IV) compounds
as anticancer agents without immediate need for synthesis. Additionally, molecular modeling is used to study DNA distortions induced by
binding metal-containing fragments derived from cisdiamminodichloroplatinum(
II) (cisplatin) and a new class of photoactive platinum
anticancer drugs. Ligand field molecular mechanics (LFMM) parameters for Pt–
guanine interactions are derived and validated against a range of experimental
structures from the Cambridge Structural Database, published quantum
mechanics/molecular mechanics (QM/MM) structures of model Pt-DNA systems
and additional DFT studies. LFMM gives a good description of the local Ptguanine
coordination at a fraction of the computational cost of QM/MM methods.
The force field is then used to develop protocols for ligand field molecular
dynamics (LFMD) simulations using experimentally characterised bifunctional
DNA adducts involving both an intra- and an interstrand crosslink of cisplatin as a
prelude to studying the interaction of trans-{Pt(py)2}2+ (P, py = pyridine), the
major 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 in
the presence of 5’-guanosine monophosphate plus the major-groove binding mode
of the monofunctional complex cis-{Pt(NH3)2(py)}2+, P is proposed to coordinate
to G7 and G19. This P-DNA adduct has a widened minor groove at one end of the
platinated site and deepened minor groove at the opposite end, and exhibits a
global bend of ~67° and an unwinding of ~20°. Brabec et al. subsequently
demonstrated experimentally that such interstrand GG crosslinks can form as a
result of the photoactivation of 17 in the presence of DNA. Such cross-links offer possibilities for specific protein–DNA interactions and suggest possible
mechanisms to explain the high potency of this photoactivated complex.
Item Type: | Thesis (PhD) | ||||
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Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RS Pharmacy and materia medica T Technology > TA Engineering (General). Civil engineering (General) |
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Library of Congress Subject Headings (LCSH): | Antineoplastic agents, Computer-aided design, Drugs -- Design, Platinum -- Therapeutic use | ||||
Official Date: | October 2011 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Department of Chemistry | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Deeth, Robert J. | ||||
Extent: | xi, 188 leaves : illustrations. | ||||
Language: | eng |
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