Chemistry Reference
In-Depth Information
In.summary,.inclusion.of.explicit.apolar.solvent.molecules.improved.the.energetic.
description.of.reactions.
I
.and.
II
..Notably,.reaction.energies.corrected.by.taking.into.
account.explicit.solvent.molecules.were.found.within.the.standard.DFT.error
94
.from.
experimental.results.
27
.Although.this.work.is.clearly.a.starting.point.for.an.extensive.
study. of. the. artiicial. nitrogen. ixation,. it. has. dual. importance.. First,. it. conirmed.
that. the. theoretical. study. of. the. Yandulov. and. Schorck. cycle. is. not. a. trivial. task.
as. explicit. solvation. cannot. be. neglected.. Thus,. if. one's. aim. is. to. describe. rigor-
ously.the.energetics.of.this.process,.improvements.to.the.proposed.solvation.model.
should. be. considered. such. as. (i). a. drastic. increase. of. the. number. of. solvent. mol-
ecules,.(ii).inclusion.of.dynamics.of.solvent.molecules,.and.(iii).temperature.effects..
This.could.be.achieved.by.using.DFT-based.QM/MM.calculations,.which.will.allow.
studying.such.large.systems.including.these.crucial.features..Second,.this.study.sug-
gests.that.widely.used.continuum.models.cannot.always.be.employed,.especially.for.
those. systems. where. speciic. solute/solvent. interactions. occur.. Since. such. interac-
tions.can.play.a.crucial.role.in.the.energetics.of.many.reactions.in.organic.solvents,.
explicit. solvent. models. may. be. required. in. other. systems. previously. investigated.
either.
in vacuo
.or.with.continuum.models.
1.3.2 P
latinum
a
nticancer
c
omPlexeS
The. most. used. metal-containing. anticancer. agent. is. cisplatin. (Figure. 1.3),. which.
is. particularly. effective. in. solid. tumors. of. testicular,. ovarian,. head. and. neck. can-
cers.
133,134
.Due.to.its.wide.range.of.applicability.in.cancer.treatment.cisplatin.is.widely.
studied.both.experimentally
134-136
.and.theoretically.
67,137-140
.Hydrolysis.and.alkylation.
reaction. rates. as. well. as. the. structural. consequences. of. cisplatin. binding. to. DNA.
are.well.understood.and.documented.
134-136,141,142
.It.is.well.known,.for.instance,.that.
cisplatin.binds.to.two.adjacent.guanines,.forming.preferentially.N7(G)-N7(G).intra-
strand.crosslinks.and.that.the.formation.of.cisplatin-DNA.adducts.induces.a.large.
kink. toward. the. major. groove,. a. local. unwinding. at. the. platinated. lesion. and. an.
increase.of.the.minor.groove.width.
142-144
.These.marked.structural.deformations.are.
recognized.by.a.series.of.proteins,.which.bind.to.the.distorted.cisplatin-DNA.adduct.
with. high. afinity.
67
. The. consequent. formation. of. cisplatin-DNA/protein. adducts.
may. inhibit. replication. and. transcription. processes,. leading. eventually. to. cell.
death.
134
.However,.repair.enzymes,.in.particular.nucleotide.excision.repair.enzymes,.
have.also.been.shown.to.interact.with.platinated.DNA.with.high.afinity..Thus,.the.
marked.structural.modiications.induced.in.double.strand.DNA.(dsDNA).by.cispla-
tin. may. be. at. the. center. of. cellular. resistance. toward. these. anticancer. drugs.
135
. In.
fact,.the.use.of.cisplatin.is.characterized.by.severe.drawbacks.such.as.intrinsic.and.
acquired.resistance.which.may.be.caused.by.the.recognition.of.the.cisplatin.lesion.
by.several.DNA-binding.proteins..In.addition,.severe.side.effects.(nausea,.ear.dam-
age.and.vomiting).occurring.upon.administration.limit.the.administered.dose.
133
.All.
these.issues.have.prompted.the.design.of.new.anticancer.drugs.ranging.from.simple.
cisplatin. derivatives,. to. more. complex. polynuclear. Pt. species,. to. drugs. containing.
different.transition.metals.
66,133,141
Focusing.on.the.problem.of.intrinsic.and.acquired.resistance.to.cisplatin.(Figure.
1.3,.
1
).and.on.a.new.generation.of.dinuclear.Pt.drugs.(Figure.1.3,.
2
.and.
3
).which.
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