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Giovanni Natile

Publications and source records attributed to Giovanni Natile.

At least 37 records · Page 2Linked to original sources
PubMed2003

X-ray structure and circular dichroism of pure rotamers of bis[guanosine-5'-monophosphate(-1)](N,N,N',N'-tetramethylcyclohexyl-1,2-diamine)platinum(II) complexes that have R,R and S,S configurations at the asymmetric diamine.

The use of a sterically hindered diamine ligand (Me(4)DACH) has allowed for the first time, the isolation and characterization, both in the solid state (X-ray crystallography) and in solution (circular dichroism), of pure DeltaHT rotamers of [Pt(Me(4)dach)(5'-GMP)(2)] (compounds 1 and 2 for R,R and S,S configurations of the Me(4)DACH ligand, respectively). Comparison of the CD spectra obtained for each rotamer, which differ only in the chirality of the Me(4)DACH ligand (R,R or S,S) or in the chirality of the HT conformation (Delta or Lambda), allowed us to conclude that, in the 200-350 nm range, the contributions to the overall CD spectrum that stem from diamine chirality and diamine-induced chirality of platinum d--d transitions or from sugar chirality are negligible relative to the exciton chiral coupling that occurs for pi-pi* transitions of the cis guanines. Accurate molecular structures of 1.10 D(2)O and 2.14 D(2)O (conventional crystallographic agreement indexes R(1) convergent to 2.07 % and 2.18 %, respectively) revealed that the crystallized rotamers have a DeltaHT conformation that is in agreement with all previously reported X-ray structures of [Pt(diamine)(nucleos(t)ide)(2)] complexes. This conformation allows the 5'-phosphate to be located in proximity to the Me(4)DACH ligand so that (P)O...HC(N) hydrogen-bond interactions exists in both complexes. For both structures, the canting of the guanine planes on the coordination plane is right-handed (R; canting angle (Phi) of 80.9 degrees and 73.2 degrees, respectively); this indicates that the canting direction is driven by the HT conformation chirality (Delta for both compounds) and not by the chirality of the carrier ligand (different for the two compounds). Density functional theory analysis of the conformational space as a function of Phi indicated a good agreement between the computed and experimental structures. The increase in energy for Phi values below 65 degrees and 55 degrees (for 1 and 2, respectively) is mainly due to the short intramolecular contacts between C(8)H and the cis N-Me groups on the same side of the platinum coordination plane.

Antineoplastic Agents↗
PubMed2003

DNA-protein cross-linking by trans-[PtCl(2)(E-iminoether)(2)]. A concept for activation of the trans geometry in platinum antitumor complexes.

The structure-pharmacological activity relationships generally accepted for antitumor platinum compounds stressed the necessity for the cis-[PtX(2)(amine)(2)] structure while the trans-[PtX(2)(amine)(2)] structure was considered inactive. However, more recently, several trans-platinum complexes have been identified which are potently toxic, antitumor-active and demonstrate activity distinct from that of conventional cisplatin (cis-[PtCl(2)(NH(3))(2)]). We have shown in the previous report that the replacement of ammine ligands by iminoether in transplatin (trans-[PtCl(2)(NH(3))(2)]) results in a marked enhancement of its cytotoxicity so that it is more cytotoxic than its cis congener and exhibits significant antitumor activity, including activity in cisplatin-resistant tumor cells. In addition, we have also shown previously that this new trans compound (trans-[PtCl(2)(E-iminoether)(2)]) forms mainly monofunctional adducts at guanine residues on DNA, which is generally accepted to be the cellular target of platinum drugs. In order to shed light on the mechanism underlying the antitumor activity of trans-[PtCl(2)(E-iminoether)(2)] we examined oligodeoxyribonucleotide duplexes containing a single, site-specific, monofunctional adduct of this transplatin analog by the methods of molecular biophysics. The results indicate that major monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] locally distort DNA, bend the DNA axis by 21 degrees toward the minor groove, are not recognized by HMGB1 proteins and are readily removed from DNA by nucleotide excision repair (NER). In addition, the monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] readily cross-link proteins, which markedly enhances the efficiency of this adduct to terminate DNA polymerization by DNA polymerases in vitro and to inhibit removal of this adduct from DNA by NER. It is suggested that DNA-protein ternary cross-links produced by trans-[PtCl(2)(E-iminoether)(2)] could persist considerably longer than the non-cross-linked monofunctional adducts, which would potentiate toxicity of this antitumor platinum compound toward tumor cells sensitive to this drug. Thus, trans-[PtCl(2)(E-iminoether)(2)] represents a quite new class of platinum antitumor drugs in which activation of trans geometry is associated with an increased efficiency to form DNA-protein ternary cross-links thereby acting by a different mechanism from 'classical' cisplatin and its analogs.

Animals↗
PubMed2003

Ground-state stability and rotational activation parameters for individual rotamers of (R,S,S,R)-(N,N'-dimethyl-2,3-diaminobutane)PtG(2) complexes (G = 9-EtG, 3'-GMP, and 5'-GMP).

Rate constants for guanine rotation about the Pt-N7 bond in (R,S,S,R)-Me(2)DABPtG(2) complexes (Me(2)DAB = N,N'-dimethyl-2,3-diaminobutane; G = 9-EtG, 3'-GMP, and 5'-GMP) were evaluated from line-shape analysis of H8 resonances. Three diastereomers, two in head-to-tail (DeltaHT and LambdaHT) and one in head-to-head (HH) conformations, exist in equilibrium in solution. The two guanines are equivalent in DeltaHT and LambdaHT conformers and nonequivalent in the HH form; therefore, four rate constants (k(Delta)(HT), k(Lambda)(HT), k(HH)()s, and k(HH)()d; sub-subscripts s and d stand for H8-shielded and -deshielded guanine, respectively) were evaluated. Activation parameters (DeltaH and DeltaS) were evaluated from the rate constant dependence on temperature. High values of DeltaH (78-93 kJ mol(-)(1)) and DeltaS (51-71 J K(-)(1) mol(-)(1)) were found for G rotation in the preferred DeltaHT rotamer having the six-membered ring of each guanine more canted toward the cis-G and a favorable dipole-dipole internucleotide interaction. Lower values of DeltaH() (64-76 kJ mol(-)(1)) and very small values of DeltaS() (-7-11 J K(-)(1) mol(-)(1)) were found for G rotation in the less favorable LambdaHT rotamer, indicating that the ground-state entropy of this rotamer is close to that of the activated complex and the ground-state enthalpy closer to that of the activated complex than for the DeltaHT rotamer. For the two guanines in the HH rotamer there is no large difference in activation parameters. In general DeltaH falls in the range 66-84 kJ mol(-)(1) (rather close to the values for the LambdaHT rotamer) and DeltaS in the range 14-41 J K(-)(1) mol(-)(1). The equilibrium constant between HT and HH rotamers was also evaluated together with the corresponding thermodynamic parameters (DeltaH and DeltaS). It is found that the low enthalpy is the major stabilizing factor for DeltaHT as compared to HH, while the entropy factor would favor the latter rotamer. In contrast the greater entropy is the stabilizing factor for the LambdaHT rotamer (the second most abundant conformer for 9-EtG and 3'-GMP) over the HH rotamer. In the latter case the enthalpy would favor the HH rotamer. In the case of the 5'-GMP derivative the greater entropy of the LambdaHT rotamer is not such to compensate for the lower enthalpy of the HH rotamer, and the latter remains the second most abundant rotamer. This investigation has allowed for the first time the enthalpic and entropic contributions favoring different rotamers to be distinguished.

Chemical Phenomena↗
PubMed2002

Formation of adenine-N3/guanine-N7 cross-link in the reaction of trans-oriented platinum substrates with dinucleotides.

The reactions of the anticancer complex trans-[PtCl2{(E)-HN=C(OMe)Me}2] (trans-EE) with a series of ribo and deoxyribodinucleotides have been studied by HPLC and 2D [1H, 15N] HMQC NMR spectroscopy and compared with those of the inactive trans isomer of cisplatin, trans-[PtCl2(NH3)2] (trans-DDP). Reactions of trans-EE with r(ApG) and d(ApG) take place through solvolysis of the starting substrate and subsequent formation of trans G-N7/monochloro and G-N7/monoaqua adducts. Slowly, the monofunctional adducts evolve to a bifunctional adduct forming an unprecedented and unexpected A-N3/G-N7 platinum cross-link spanning two trans positions. For stereochemical reasons, trans platinum complexes cannot form N7/N7 cross-links between adjacent purines in di- or polynucleotides. For the reverse sequence r(GpA), no chelate structure was formed even after a two-week reaction. The reaction of trans-DDP with r(ApG) produces many more products than the analogous reaction with trans-EE. One of these products was identified as the A-N3/G-N7 trans-chelate.

Adenine↗
PubMed2002

Factors influencing conformer equilibria in retro models of cisplatin-DNA adducts as revealed by moderately dynamic (N,N'-dimethyl-2,3-diaminobutane)PtG(2) retro models (G = a guanine derivative).

Typical cis-PtA(2)G(2) models of key DNA lesions formed by cis-type Pt anticancer drugs are very dynamic and difficult to characterize (A(2) = diamine or two amines; G = guanine derivative). Retro models have A(2) carrier ligands designed to decrease dynamic motion without eliminating any of three possible conformers with bases oriented head-to-tail (two: DeltaHT and LambdaHT) or head-to-head (one: HH). All three were found in NMR studies of eight Me(2)DABPtG(2) retro models (Me(2)DAB = N,N'-dimethyl-2,3-diaminobutane with S,R,R,S and R,S,S,R configurations at the chelate ring N, C, C, and N atoms, respectively; G = 5'-GMP, 3'-GMP, 5'-IMP, and 3'-IMP). The bases cant to the left (L) in (S,R,R,S)-Me(2)DABPtG(2) adducts and to the right (R) in (R,S,S,R)-Me(2)DABPtG(2) adducts. Relative to the case in which the bases are both not canted, canting will move the six-membered rings closer in to each other ("6-in" form) or farther out from each other ("6-out" form). Interligand interactions between ligand components near to Pt (first-first sphere communication = FFC) or far from Pt (second-sphere communication = SSC) influence stability. In typical cases at pH < 8, the "6-in" form is favored, although the larger six-membered rings of the bases are close. In minor "6-out" HT forms, the proximity of the smaller five-membered rings could be sterically favorable. Also, G O6 is closer to the sterically less demanding NH part of the Me(2)DAB ligand, possibly allowing G O6-NH hydrogen bonding. These favorable FFC effects do not fully compensate for possibly stronger FFC dipole effects in the "6-in" form. SSC, phosphate-N1H cis G interactions favor LambdaHT forms in 5'-GMP and 5'-IMP complexes and DeltaHT forms in 3'-GMP and 3'-IMP complexes. When SSC and FFC favor the same HT conformer, it is present at >90% abundance. In six adducts [four (S,R,R,S)-Me(2)DABPtG(2) and (R,S,S,R)-Me(2)DABPtG(2) (G = 3'-GMP and 3'-IMP)], the minor "6-out" HT form at pH approximately 7 becomes the major form at pH approximately 10, where G N1H is deprotonated, because the large distance between the negatively charged N1 atoms minimizes electrostatic repulsion and probably because the G O6-(NH)Me(2)DAB H-bond (FFC) is strengthened by N1H deprotonation. At pH approximately 10, phosphate-negative N1 repulsion is an unfavorable SSC term. This factor disfavors the LambdaHT R form of two (R,S,S,R)-Me(2)DABPtG(2) (G = 5'-GMP and 5'-IMP) adducts to such an extent that the "6-in" DeltaHT R form remains the dominant form even at pH approximately 10.

Chemical Phenomena↗
PubMed2002

Differential genotoxic effects of antitumor trans-[PtCl(2)(E-iminoether)(2)] and cisplatin in Escherichia coli.

In the present work, we measured survival and the platinum on the genome after treatment of repair-proficient or repair-deficient Escherichia coli strains with trans-[PtCl(2)(E-iminoether)(2)] and compared these results with the effects of "classical" cisplatin. We found that toxicity of antitumor trans-[PtCl(2)(E-iminoether)(2)] in repair-deficient trains was much less than that of cisplatin. This markedly reduced toxicity was not a consequence of the reduced uptake or low levels of DNA binding in the bacteria cells but rather appeared to reflect DNA binding mode of this trans-platinum drug different from that of cisplatin.

Antineoplastic Agents↗
PubMed2002

Direct addition of alcohols to organonitriles activated by ligation to a platinum(IV) center.

Treatment of trans-[PtCl(4)(RCN)(2)] (R = Me, Et) with R'OH (R' = Me, Et, n-Pr, i-Pr, n-Bu) at 45 degrees C in all cases allowed the isolation of the trans-[PtCl(4)[(E)-NH=C(R)OR'](2)] imino ester complexes, while the reaction between cis-[PtCl(4)(RCN)(2)] and the least sterically hindered alcohols (methanol and ethanol) results in the formation of cis-[PtCl(4)[(E)-NH=C(R)OR'](2)] (R/R' = Me/Me) or trans-[PtCl(4)[(E)-NH=C(Et)OR'](2)] (R' = Me, Et), the latter being formed via thermal isomerization (ROH, reflux, 3 h) of the initially formed corresponding cis isomers. The reaction between alcohols R'OH and cis-[PtCl(4)(RCN)(2)] (R = Me, R' = Et, n-Pr, i-Pr, n-Bu; R = Et; R' = n-Pr, i-Pr, n-Bu), exhibiting greater R/R' steric congestion, allowed the isolation of cis-[PtCl(4)[(E)-NH=C(R)OR'][(Z)-NH=C(R)OR']] as the major products. The alcoholysis reactions of poorly soluble [PtCl(4)(RCN)(2)] (R = CH(2)Ph, Ph) performed under heterogeneous conditions, directly in the appropriate alcohol and for a prolonged time and, for R = Ph, with heating led to trans-[PtCl(4)[(E)-NH=C(R)OR'](2)] (R = CH(2)Ph, R' = Me, Et, n-Pr, i-Pr; R = Ph, R' = Me) isolated in moderate yields. In all of the cases, in contrast to platinum(II) systems, addition of R'OH to the organonitrile platinum(IV) complexes occurs under mild conditions and does not require a base as a catalyst. The formed isomerically pure (imino ester)Pt(IV) complexes can be reduced selectively, by Ph(3)P=CHCO(2)Me, to the corresponding isomers of (imino ester)Pt(II) species, exhibiting antitumor activity, without change in configuration of the imino ester ligands. Furthemore, the imino esters NH=C(R)OR' can be liberated from both platinum(IV) and platinum(II) complexes [PtCl(n)[H=C(R)OR'](2)] (n = 2, 4) by reaction with 1,2-bis(diphenylphosphino)ethane and pyridine, respectively. All of the prepared compounds were characterized by elemental analyses (C, H, N), FAB mass spectrometry, IR, and (1)H, (13)C[(1)H], and (195)Pt (metal complexes) NMR spectroscopies; the E and Z configurations of the imino ester ligands in solution were determined by observation of the nuclear Overhauser effect. X-ray structure determinations were performed for trans-[PtCl(4)[(E)-NH=C(Me)OEt](2)] (2), trans-[PtCl(4)[(E)-NH=C(Et)OEt](2)] (10), trans-[PtCl(4)[(E)-NH=C(Et)OPr-i](2)] (11), trans-[PtCl(4)[(E)-NH=C(Et)OPr-n](2)] (12), and cis-[PtCl(4)[(E)-NH=C(Et)OMe](2)] (14). Ab initio calculations have shown that the EE isomers are the most stable ones for both platinum(II) and platinum(IV) complexes, whereas the most stable configurations for the ZZ isomers are less stable than the respective EZ isomers, indicating an increase of the stability on moving from the ZZ to the EE configurations which is more pronounced for the Pt(IV) complexes than for the Pt(II) species.

Journal Article↗
PubMed2002

Modification of second-sphere communication, leading to an unusually high abundance of the head-to-head conformer of cisplatin cross-link retro models.

Rapid atropisomerization of cisplatin-DNA cross-link models, cis-PtA(2)G(2) (A(2) = two amines or a diamine, G = guanine derivative, bold font indicating a guanine not linked to another guanine), makes their NMR spectra uninformative. The conformers [two head-to-tail (DeltaHT and LambdaHT) conformers, one head-to-head (HH) conformer] are detected in (CCC)PtG(2) retro models (CCC = chirality-controlling chelates designed to reduce rotation around the G N7 to Pt bond by destabilizing the transition state). Clear trends are found with four CCC ligands, 2,2'-bipiperidine (Bip) and N,N'-dimethyl-2,3-diaminobutane (each with S,R,R,S and R,S,S,R configurations at the chelate ring N, C, C, and N atoms, respectively). S,R,R,S ligands favor left-handed G base canting and the LambdaHT form; R,S,S,R ligands favor right-handed canting and the DeltaHT form. The HH conformer is normally negligible unless G = 5'-GMP. However, understanding this 5'-phosphate effect is complicated by possible interligand interactions of the 5'-phosphate with the N1H of the cis-5'-GMP and a CCC NH; these interactions are referred to as second-sphere (SSC) and first-to-second-sphere (FSC) communication, respectively. We now investigate the four (CCC)PtG(2) models with 1-Me-5'-GMP, a G lacking the N1H needed for SSC. The phosphate location makes FSC possible in the major but not the minor HT form. The major form should increase from pH 3 to pH 7 because the phosphate is deprotonated at pH 7. However, the major DeltaHT form for the R,S,S,R pair did not change in abundance, and the major LambdaHT form for the S,R,R,S pair actually decreased. Thus, FSC is weak. At pH approximately 7 the HH conformer of the S,R,R,S pair had an abundance (40-44%) higher than that in any reported cis-PtA(2)G(2) adduct. FSC involving one 1-Me-5'-GMP could play a role. The high HH abundance and use of a pH jump experiment with (S,R,R,S)-BipPt(1-Me-5'-GMP)(2) allowed us to obtain the first deconvoluted CD spectrum for a cis-PtA(2)G(2) HH conformer. The CD features for the HH conformer are much weaker than for the HT conformers. Our findings are best interpreted to indicate that FSC is not important in aqueous solution, especially for the HT form. Weak FSC is consistent with recent models of the cross-link in duplexes. In contrast, crystals of fluxional models often reveal FSC, but not the more important SSC. SSC was unrecognized until our retro model studies, and the new results reinforce the value of studying retro models for identifying interactions in solution.

Chemical Phenomena↗
PubMed2002

X-ray structures of the first platinum complexes with Z configuration iminoether ligands: trans-dichlorobis(1-imino-1-methoxy-2,2'-dimethylpropane)platinum(II) and trans-tetrachlorobis(1-imino-1-methoxy-2,2'-dimethylpropane)platinum(IV).

Platinum complexes with Z configuration iminoether ligands (trans-[PtCl(2)(HN=C(OMe)Bu(t))(2)], 1, and trans-[PtCl(4)(HN=C(OMe)Bu(t))(2)], 2) have been structurally characterized for the first time. The nearly planar Pt-N-C-O-C chain, all atoms being in gauche conformation, brings the terminal Pt and C atoms very close to one another. The steric clash is released by considerably increasing the Pt-N-C, N-C-O, and C-O-C bond angles (133, 124, and 121 degrees for 1, respectively; 147, 129, and 127 degrees for 2, respectively), which are well above the expected values (120 degrees for Pt-N-C and N-C-O; less than 120 degrees for C-O-C owing to the repulsive effect exerted by the lone pair of electrons on the oxygen atom). In the platinum(II) case the smaller increase of bond angles is accompanied by a greater value of the Pt-N-C-O torsion angle (27.3 and 15.6 degrees for 1 and 2, respectively). The stabilization of the Z configuration, notwithstanding the steric clashes described above, has been achieved by a careful choice of the R substituent in the iminoether moiety (a bulky tert-butyl group). The reactions of the platinum(IV) species (2) in basic and acidic conditions and with triphenylphosphine have been investigated. Bases and acids both interact with the coordinated ligand in such a way to weaken the coordinative bond and promote the release of the iminoether ligands. The phosphine promotes a ready and complete reduction of the platinum(IV) complex to the corresponding platinum(II) species (1). Compound 1 reacts with a stoichiometric amount of phosphine (1:1 molar ratio) to form cis-[PtCl(2)(PPh(3))(Z-HN=C(OMe)Bu(t))] and with excess phosphine to form [PtCl(2)(PPh(3))(2)] and free iminoether. The latter two reactions leading to formation of a mixed phosphine/iminoether platinum species and to free iminoether, which can be used as a synthon for further organic transformations, can be of synthetic utility.

Journal Article↗
PubMed2002

Recognition of major DNA adducts of enantiomeric cisplatin analogs by HMG box proteins and nucleotide excision repair of these adducts.

We examined HMG domain protein recognition of major 1,2-GG intrastrand DNA crosslinks, formed by two bifunctional enantiomeric analogs of antitumor cis-diamminedichloroplatinum(II) (cisplatin), and removal of these crosslinks during in vitro nucleotide excision repair (NER) reactions. Electrophoretic mobility shift assays show that domains A and B of HMGB1 protein bind to (2R,3R)-diaminobutanedichloroplatinum(II)-generated crosslinks with a higher affinity than to those generated by (2S,3S)-diaminobutanedichloroplatinum(II). The crosslinks of both enantiomers are removed by NER with a similar efficiency; however, HMG1B protein significantly inhibits removal of the (2R,3R)-diaminobutaneplatinum(II) adduct, but not that of the (2S,3S) enantiomer. Thus, HMG domain proteins discriminate among different conformations of the 1,2-GG intrastrand crosslinks of the two enantiomeric analogs of cisplatin, which results in different NER of these crosslinks. This observation may provide insight into the mechanisms underlying antitumor activity of cisplatin and its analogs.

Animals↗
PubMed2002

Chiral discrimination in platinum anticancer drugs.

In this article we review the biological activity of analogs of the antitumor drug cisplatin that contain chiral amine ligands. Interaction with DNA and formation of cross-links with adjacent purine bases are considered to be the crucial steps in the antitumor activity of this class of complexes. Because double-helical DNA has a chiral structure, interaction with enantiomeric complexes of platinum should lead to diastereomeric adducts. It has been demonstrated that DNA cross-links of platinum complexes with enantiomeric amine ligands not only can exhibit different conformational features but also can be processed differently by the cellular machinery as a consequence of these conformational differences. These results expand the general knowledge of how the stereochemistry of the platinum-DNA adduct can influence the cell response and contribute to understanding the processes that are crucial for antitumor activity. The steric requirements of the chiral ligands, in terms of configuration and flexibility, are also elucidated.

Antineoplastic Agents↗
PubMed2001

Antitumor trans Platinum Complexes can Form Cross-Links with Adjacent Purine Groups Financial support by the European Commission BIOMED II program (Contract BMH4-CT97-2485) and COST (D8/007/97 and D8/012/97) are gratefully acknowledged. Thanks are extended to the Norwegian Research Council (Contract 135055/410), the University of Bari, the Ministero dell'Università e della Ricerca Scientifica e Tecnologica, MURST (Cofin. 1988 no. 9803021072), and the Consiglio Nazionale delle Ricerche, CNR (Roma) for financial support.

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Journal Article↗
PubMed1999

Retro Models of Pt Anticancer Drug DNA Adducts: Chirality-Controlling Chelate Ligand Restriction of Guanine Dynamic Motion in (2,2'-Bipiperidine)PtG(2) Complexes (G = Guanine Derivative).

Features of cisplatin-type anticancer drug adducts with nucleic acids and their constituents are clouded because they exist as a fluxional mixture of conformers. Retro-model adducts containing the specially designed chiral diamine ligand, Bip = 2,2'-bipiperidine, are dramatically less fluxional. Conformers of BipPtG(2) adducts with R,S,S,R and S,R,R,S asymmetric centers at the N, C, C, and N Bip chelate ring atoms and G = 5'-GMP, 5'-dGMP, 3'-GMP, or 9-ethylguanine are amenable to separate characterization. All possible BipPtG(2) atropisomers (one head-to-head (HH) and Delta and Lambda head-to-tail (HT) atropisomers) were observed by NMR spectroscopy. At equilibrium at low pH, one HT atropisomer dominates. CD spectra, G H8 chemical shifts, and low-pH equilibria of BipPtG(2) and Me(2)()DABPtG(2) (Me(2)()DAB = N,N '-dimethyl-2,3-diaminobutane) are similar when the chelate ring atoms have the same stereochemistries; thus, Bip and Me(2)()DAB are termed chirality-controlling chelates (CCC) since these ligands dictate the absolute conformation of the major HT rotamer. In each case, the HT conformer that cannot form G O6-NH(CCC) hydrogen bonds was dominant, and the G H8 chemical shift indicated that this conformer had less tilted bases, allowing favorable base-base dipole-dipole interactions. For both the R,S,S,R and S,R,R,S Bip chiralities of the BipPt(3'-GMP)(2) complexes, the percentage of DeltaHT rotamer increased near pH 7, a probable consequence of phosphate-cis-G hydrogen bonds accompanied by favorable dipole interactions of less tilted bases. For the 5'-GMP complexes, these factors favor the LambdaHT rotamer near pH 7. When G has a 5'-phosphate group, rotamer distribution is also influenced by phosphate-NH(Bip) hydrogen bonds. At high pH, the nature and/or strength of interactions such as G dipole-G dipole interactions and G O6-NH(Bip) and phosphate-cis-G hydrogen bonding are altered by G N(1)H deprotonation. The features of the complexes at high pH can be largely explained as arising from the net result of these interactions. This information from retro models with a CCC ligand lays the foundation for understanding and evaluating the properties of the highly dynamic adducts of anticancer drugs.

Journal Article↗
PubMed1999

Diminishing Dynamic Motion Problems of Platinum Anticancer Drug Adducts of Guanine Derivatives with the Hybrid Ligand Approach: Evidence for Cis Interligand Interactions Especially between 3'-GMP's.

The key problem obscuring the role of the ammine and primary amine groups in the activity of clinically used Pt anticancer drugs is the dynamic character of adducts with DNA and DNA constituents. To address this problem, we introduced the hybrid ligand approach with the diamine pipen = 2-(aminomethyl)piperidine; the piperidine ring greatly reduces dynamic motion in adducts. We now use NMR and CD methods to investigate (S,R)- and (R,S)-pipenPtG(2) complexes (with S,R and R,S configurations at the N and C pipen asymmetric centers, respectively; G = a guanine derivative). Each pipenPtG(2) complex can have two head-to-head (HH) and two head-to-tail (HT) rotamers. However, only the two HT atropisomers were detected. The Delta or Lambda chirality of each HT rotamer was determined from NOESY/EXSY spectra and/or the sign of the CD signal. Examination of adducts with G = 5'-GMP, 3'-GMP, or 9-EtG (9-ethylguanine) allowed us to assess the effects of different N9 substituents and pipen chirality on the stability and spectral properties of the atropisomers. For the 9-EtG complexes, the HT atropisomers were nearly equally stable, indicating that the pipen configuration has little influence when the N9 substituent lacks a phosphate group. However, for GMP complexes, several factors influence both relative abundance and shifts of the H8 signals of the DeltaHT and LambdaHT forms at neutral pH. The chirality of the major HT form of the (S,R)- and (R,S)-pipenPt(5'-GMP)(2) complexes was Lambda and Delta, respectively. Therefore, the chirality of the pipen ligand is an important determinant of HT chirality for pipenPt(5'-GMP)(2). Since, for 5'-GMP, phosphate-NH(pipen) hydrogen bonding is possible, this interaction probably favors the major atropisomer, in which two such interactions are possible, over the minor atropisomer, in which only one interaction is possible. The DeltaHT form was dominant for both (S,R)- and (R,S)-pipenPt(3'-GMP)(2). The stability arises from the more favorable interactions between the phosphates and the NH's of the cis 3'-GMP's in the DeltaHT vs the LambdaHT form. This hydrogen bonding is more favorable when the G bases have less tilt, and less tilted G's are associated with more favorable dipole-dipole interactions and deshielded H8 signals. We showed that 3'-GMP adducts favor the DeltaHT conformer at pH7; the DeltaHT conformer preference explains the enhanced "Delta" CD signal observed for most 3'-GMP adducts, including the cisplatin adduct.

Journal Article↗
PubMed1999

New Steric Hindrance Approach Employing the Hybrid Ligand 2-Aminomethylpiperidine for Diminishing Dynamic Motion Problems of Platinum Anticancer Drug Adducts Containing Guanine Derivatives.

A fundamental problem obscuring the role of the ammine and primary amine groups in the activity of clinically used Pt anticancer drugs is the dynamic character of the adducts with DNA and DNA constituents. Dynamic motion is slower in analogues containing only secondary or tertiary amines, but such agents are not used clinically. Recently we found that enclosing the N center within a piperidine (pip) ring greatly reduces dynamic motion. In this work, we test the hypothesis that a diamine with only one pip ring, 2-aminomethylpiperidine (pipen), would slow dynamic motion enough for insightful study of adducts with one site (cis to the primary amine) closely reflecting the coordination environment of clinically used drugs. Racemic pipen was prepared and resolved by improved methods. PtCl(2)(pipen) synthesized with the pipen enantiomer having an R configuration of the asymmetric carbon (determined on the basis of the [alpha](D) sign) has the S stereochemistry at the N asymmetric center. In the adduct (S,R)-pipenPt(5'-GMP)(2), restricted rotation of the two nonequivalent N7-coordinated 5'-GMP's about the Pt-N7 bonds potentially could lead to two head-to-tail (LambdaHT and DeltaHT) and two head-to-head (HH(1) and HH(2)) atropisomers. However, 1D and 2D NOESY NMR data at pH approximately 3 indicated the dominance of the two HT atropisomers in a LambdaHT:DeltaHT ratio of 2:1. Deprotonation of the phosphate group (pH 7) further stabilized the LambdaHT form, and the CD signal had the shape characteristic of a LambdaHT form with a positive peak at approximately 280 nm. However, at pH 9.5, where the 5'-GMP N1H was largely deprotonated, the NMR spectrum and the approximately 280 nm CD peak both revealed that the LambdaHT form had decreased. When the pH was jumped down to 6.9, the NMR signals of the LambdaHT form and the approximately 280 nm CD peak increased with a half-time of approximately 3 min. Thus, the pip ring lengthens the atropisomerization time from seconds for ethylenediaminePt(5'-GMP)(2) to minutes for (S,R)-pipenPt(5'-GMP)(2). This pH jump experiment indicates that the signs of the CD signal are opposite for the LambdaHT and DeltaHT forms. Changes with pH in both the relative abundance and shifts of the H8 signals of the LambdaHT and DeltaHT forms correlated with an increase in hydrogen bonding by the phosphate group of the 5'-GMP cis to the primary amine. The hydrogen bonding changes the 5'-GMP base tilt and hence the H8 chemical shift. Such information is not obtainable on 5'-GMP adducts of clinically used anticancer drugs.

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PubMed1998

Chirality-Controlling Chelate (CCC) Ligands in Analogues of Platinum Anticancer Agents. Influence of N9 Substituents of Guanine Derivatives (G) on the Distribution of Chiral Conformers of (CCC)PtG(2) with CCC = N,N'-Dimethyl-2,3-diaminobutane.

Chirality-controlling chelate (CCC) ligands are a class of chiral diamine ligands with one or two chiral secondary amine ligating groups. Analogues of platinum anticancer agents containing CCC ligands exhibit unusual steric and dynamic features. In this study NMR and CD methods were used to evaluate the influence of the N9 substituent in guanine derivatives (G) on conformer distribution in one class of (CCC)PtG(2)() complexes. We employed the CCC ligand, N,N'-dimethyl-2,3-diaminobutane [Me(2)()DAB with S,R,R,S or R,S,S,R configurations at the four asymmetric centers, N, C, C, and N]. For each Me(2)()DABPtG(2) complex, the presence of four G H8 signals demonstrated formation of all three possible atropisomers: DeltaHT (head-to-tail), LambdaHT, and HH (head-to-head). Different G ligands (5'-GMP, 3'-GMP, 1-MeGuo, Guo, or 9-EtG) were chosen to assess the effect of the N9 substituent on the relative stability and spectral properties of the atropisomers. The conformations of the atropisomers of Me(2)()DABPtG(2) were determined from CD spectra and from NOE cross-peaks (assigned via COSY spectra) between G H8 signals and those for the Me(2)()DAB protons. Regardless of the N9 substituent, the major form was HT. However, this form had the opposite chirality, LambdaHT and DeltaHT, and base tilt direction, left- and right-handed, respectively, for the S,R,R,S and R,S,S,R configurations of the Me(2)()DAB ligand. Thus, the chirality of the CCCligand, not hydrogen bonding, is the most important determinant of conformation. For each Me(2)()DABPtG(2) complex, the tilt direction of all three atropisomers is the same and, except for 5'-GMP, the order of abundance was major HT > minor HT > HH. For 5'-GMP, the HH atropisomer was three times as abundant as the minor HT species, suggesting that phosphate-NH(Me(2)()DAB) hydrogen bonds could be present since such bonding is possible only for the 5'-GMP derivatives. However, if such phosphate-NH hydrogen bonds exist, they are weak since the percentage of the major HT form of 5'-GMP complexes is similar and indeed can be smaller compared to this percentage for complexes with other G's. The CD spectra of all (S,R,R,S)-Me(2)()DABPtG(2) complexes were similar and opposite to those of all (R,S,S,R)-Me(2)()DABPtG(2) complexes, indicating the CD signature is characteristic of the dominant HT conformer, which has a chirality dictated by the chirality of the CCC ligand and not the N9 substituent.

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PubMed1997

Factors Influencing the Configuration and Conformation of Diamine Chelate Rings in Platinum(II) Compounds: 2,4-Bis(methylamino)pentane Complexes.

Complexes of the type [PtX(2)(Me(2)DAP)] (Me(2)DAP = 2,4-bis(methylamino)pentane) have been prepared and studied by (1)H NMR spectroscopy, molecular mechanics/dynamics (MMD) calculations, and X-ray crystallography. The coordinated Me(2)DAP ligand has four asymmetric centers. Complexes with an enantiomeric form of the ligand (e.g., RR-Me(2)DAP, RR being the configurations of the two asymmetric carbons) have three possible configurations, namely, SRRR, RRRR, and SRRS at N, C, C, and N, respectively. Indeed these three isomers were obtained in respective ratios of 9:1: approximately 0 for X = I(-) and of 7:3:1 for X = Cl(-). Complexes with the meso ligand (RS-Me(2)DAP) have four possible configurations, i.e., SRSR, RRSS, RRSR, and SRSS at N, C, C, and N, respectively (the latter two constitute an enantiomeric pair). Only the two symmetrical isomers were obtained in the ratios of 9:1 for X = I(-) and 1:1 for X = Cl(-). In addition, the preferred chelate ring conformations in solution (CDCl(3)) were determined to be the following: delta-chair (SRRR), lambda-skew (RRRR), fluxional chair (SRRS), fluxional skew (SRSR), and lambda-chair (RRSS). This information was used to assess the contributions of intra- and interligand interactions to determine the conformational stability. MMD calculations employing the AMBER force field [as modified by Yao et al. (Yao, S.; Plastaras, J. P.; Marzilli, L. G. Inorg. Chem. 1994, 33, 6061) and extended to include parameters for the Cl(-) ligands] provided minimum-energy structures for all five X = Cl(-) complexes. These structures agreed well with the experimentally determined solution conformations except for SRSR, which had a lowest energy delta-chair instead of skew conformation. X-ray structural studies of the SRSR species (X = Cl(-) and X = I(-)) confirmed the delta-chair conformation. The results suggest that an equatorial N-methyl group has nonbonded clashes with the cis chloride ligand; therefore, axial N-methyl groups are favored. However, in solution, the solvent and entropy (connected with fluxionality of conformers) are factors which, to some degree, can overcome the interligand steric interaction.

Journal Article↗
PubMed1996

Steric Crowding and Redox Reactivity in Platinum(II) and Platinum(IV) Complexes Containing Substituted 1,10-Phenanthrolines.

The effect of the phenanthroline substituents on the structure and reactivity of platinum(II) and platinum(IV) complexes has been investigated. The X-ray crystal structures of the compounds [PtI(2)(4,7-Ph(2)phen)].CHCl(3) (1dz.CHCl(3)), [PtI(4)(4,7-Ph(2)phen)].CHCl(3) (2dz.CHCl(3)), [PtI(2)(2,9-Me(2)-4,7-Ph(2)phen)] (1fz), and [PtI(4)(2,9-Me(2)-4,7-Ph(2)phen)].I(2) (2fz.I(2)) have shown that complexes 1fz and 2fz, containing ortho-substituted phenanthrolines, exhibit a remarkable displacement of the equatorial iodine atoms from the N-Pt-N' plane (average 0.477(2) and 0.199(2) Å, respectively), a bending of the phenanthroline [angle between outer rings of 19.9(7) and 14.2(7) degrees, respectively] and a rotation of the N-C-C'-N' plane with respect to the N-Pt-N' plane [32.3(10) and 26.5(9) degrees, respectively]. Comparison between the structures of 1fz and 2fz, both having the phenanthroline with methyl substituents in the ortho position, indicates that, in the latter case, because of the presence of the two axial iodine ligands, the displacements of the ligands from the equatorial plane are smaller and find a compensation in a narrowing of the I(1)-Pt-I(1') angle (5 degrees ) and a lengthening of the Pt-N bonds (0.07 Å). The electrochemical behavior of the four-coordinate platinum(II) complexes shows that compounds possessing regular planar geometry have access to the one-electron reduced species, whereas those with distorted coordination geometry are irreversibly reduced by collapsing of the complex geometry. This is in sharp contrast with the behavior of related nickel complexes for which the pseudo-tetrahedral coordination imposed by bulky 2,9-substituents of phenanthroline stabilizes the nickel(I) species. Spectroscopic results allow us to assign a significant Pt(I) character to [1d](-) monoanions. The electrogenerated, plus one electron, complexes are not indefinitely stable and, because of conjugation with the phen ligand, progressively restore the Pt(II) oxidation state by transferring the electron to the peripheral organic ligand. The latter process can involve multiple electron additions in the macroelectrolysis time scale. The related platinum(IV) complexes [PtX(4)(L)] undergo irreversible two-electron reduction accompanied by fast release of the axial ligands and formation of the corresponding platinum(II) species.

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