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Transplatin is an inactive platinum drug; however, a number of analogues, such as trans-EE and trans-PtTz, demonstrate promising antitumor activity in vitro and in vivo. Although the ultimate target is nuclear DNA, increasing evidence indicate that proteins also play important roles in the display of antitumor activity. The linker histone H1 is situated by the portal between the unwrapped DNA and the nucleosome core. Our recent study revealed that H1 can readily react with cisplatin, and the adducts tend to form ternary complexes with DNA. In this work, we have investigated the reaction of histone H1 with two antitumor-active trans-oriented complexes, trans-EE and trans-PtTz, and the effect of H1 upon the platination of DNA. The results show that trans-platinum drugs are much more reactive than cisplatin toward H1. Interestingly, in addition to the expected bidentate adducts (by displacement of the two labile chlorido ligands), also a tridentate adduct can be formed by displacement of one nonlabile carrier ligand of trans-EE or trans-PtTz. The trans-Pt/H1 adducts can then react with DNA and generate protein-Pt-DNA ternary complexes. Additionally, platinum can be transferred from trans-Pt/H1 adducts to DNA, generating binary trans-Pt/DNA complexes. Such a transfer of the platinum agent to DNA was not observed in the reaction of cisplatin. Furthermore, the detailed investigation carried out on a model peptide indicates that H1 promotes the DNA platination by trans- EE, while it reduces that of trans-PtTz and cisplatin. These results suggest that H1 can play a key role in the DNA platination and modulate the efficacy of different platinum agents.

Two new Pt(II) derivatives of kiteplatin ([PtCl 2 (cis-1,4-DACH)]) with pyrophosphate as carrier ligand, one mononuclear (1) and one dinuclear (2), were synthesized with the aim of potentiating the efficacy of kiteplatin. Complex 1 resulted to be remarkably stable at physiological pH, but it undergoes a fast hydrolysis reaction at acidic pH releasing free pyrophosphate and (aquated) kiteplatin. The dinuclear compound 2 resulted to be less stable than 1 at both neutral and acidic pH forming 1 and (aquated) kiteplatin as first step. Both compounds (1 and 2) do not react as such with 5'-GMP, whereas their hydrolysis products readily form adducts with the nucleotide. The in vitro cytotoxicity assays against a panel of six human cancer cell lines showed that complex 2 affects cancer cell viability even at nanomolar concentrations. The cytotoxic activity of 2 is greater (up to 2 orders of magnitude) than that of cisplatin, oxaliplatin, and kiteplatin, whereas the mononuclear complex 1 has shown a cytotoxic activity comparable to that of oxaliplatin and kiteplatin, but higher than cisplatin. The latter result is not surprising, since the presence of two negative charges reduces the uptake of 1 into the tumor cells as compared to the neutral compound 2. The remarkable activity of 2 against the pancreatic cell line BxPC3 (average IC 50 = 0.07 μM) deserves further investigation.

One concept how to improve anticancer effects of conventional metallodrugs consists in conjugation of these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, biological effects, and mechanisms of action of new Pt(II) derivatives containing one or two nonsteroidal anti-inflammatory diclofenac (DCF) ligands also known for their antitumor effects. The antiproliferative properties of these metallic conjugates show that these compounds are potent and cancer cell selective cytotoxic agents exhibiting activity in cisplatin resistant and the COX-2 positive tumor cell lines. One of these compounds, compound 3, in which DCF molecules are coordinated to Pt(II) through their carboxylic group, is more potent than parental conventional Pt(II) drug cisplatin, free DCF and the congeners of 3 in which DCF ligands are conjugated to Pt(II) via a diamine. The potency of 3 is due to several factors including enhanced internalization that correlates with enhanced DNA binding and cytotoxicity. Mechanistic studies show that 3 combines multiple effects. After its accumulation in cells, it releases Pt(II) drug capable of binding/damaging DNA and DCF ligands, which affect distribution of cells in individual phases of the cell cycle, inhibit glycolysis and lactate transport, collapse mitochondrial membrane potential, and suppress the cellular properties characteristic of metastatic progression.

Copper trafficking proteins have been implicated in the cellular response to platinum anticancer drugs. We investigated the reaction of the chaperone Atox1 with an activated form of oxaliplatin, the third platinum drug to reach worldwide approval. Unlike cisplatin, which contains monodentate ammines, oxaliplatin contains chelated 1,2-diaminocyclohexane (DACH), which is more resistant to displacement by nucleophiles. In solution, one or two {Pt(DACH)(2+)} moieties bind to the conserved CXXC metal-binding motif of Atox1; in the latter case the two sulfur atoms likely bridging the two platinum units. At longer reaction times, a dimeric species is formed whose composition, Atox12·Pt(2+)2, indicates complete loss of the diamine ligands. Such a dimerization process is accompanied by partial unfolding of the protein. Crystallization experiments aiming at the characterization of the monomeric species have afforded, instead, a dimeric species resembling that already obtained by Boal and Rosenzweig in a similar reaction performed with cisplatin. However, while in the latter case there was only one Pt-binding site (0.4 occupancy) made of four sulfur atoms of the CXXC motifs of the two Atox1 chains in a tetrahedral arrangement, we found, in addition, a secondary Pt-binding site involving Cys41 of the B chain (0.25 occupancy). Moreover, both platinum atoms have lost their diamines. Thus, there appears to be little relationship between what is observed in solution and what is formed in the solid state. Since full occupancy of the tetrahedral cavity is a common feature of all Atox1 dimeric structures obtained with other metal ions (Cu(+), Cd(2+), and Hg(2+)), we propose that in the case of platinum, where the occupancy is only 0.4, the remaining cavities are occupied by Cu(+) ions. Experimental evidence is reported in support of the latter hypothesis. Our proposal represents a meeting point between the initial proposal of Boal and Rosenzweig (0.4 Pt occupancy) and the reinterpretation of the original crystallographic data put forward by Shabalin et al. (1 Cu occupancy), and could apply to other cases.

Iminoether derivatives of the formula trans-[PtCl2{HN═C(R)OR'}2] proved to be endowed with remarkable antitumor activity in vivo. Moreover, these trans compounds were more cytotoxic than their cis congeners, a trend opposite to that generally observed for corresponding platinum complexes with ammines. The imino ligands can have either E or Z configuration about the C═N double bond, and in the case of R = R' = Me, the E configuration is by far thermodynamically preferred. However, substitution of chloride anions with neutral ligands (L) alters the relative stability of the E and Z isomers. Upon investigation of the derivatives with L = PPh3, AsPh3, Me2S═O, and (H2N)2C═S, it has been concluded that an electrostatic interaction between the oxygen lone pair of the iminoether and the platinum center, fostered by the net positive charge of the complex and the low dielectric constant around the metal core provided by the hydrophobic L ligands, stabilizes the Z configuration. The same factors can favor iminoether isomerization. These conclusions are fully supported by X-ray crystal data. In the case of a reaction with thiourea, an aminic group of thiourea can substitute the methoxy group of a cis-iminoether, leading to the formation of a cyclic compound in a process reminiscent of the McLafferty rearrangement. Such a rearrangement could play a role in the interaction of the platinum-iminoether compounds with target DNA and proteins.

The initial aim of the present work was the synthesis of the axial disuccinato Pt(IV) derivative of [PtCl2(cis-1,4-DACH)] (Kiteplatin, 1 in Figure 1 ) (DACH = diaminocyclohexane), which contains an isomeric form of the diamine ligand present in oxaliplatin (i.e., 1R,2R-DACH). The interest in this compound stems from its activity on several cisplatin and oxaliplatin-resistant cell lines. Oxidation of 1 with hydrogen peroxide affords cis,trans,cis-[PtCl2(OH)2(cis-1,4-DACH)] (2) which was treated with succinic anhydride in suitable solvents. To our surprise, in dimethylformamide (DMF) (50-70 °C or under light irradiation) or in dimethylsulfoxide (DMSO) (under light irradiation) the formation of the succinato complex cis,trans,cis-[PtCl2{OC(O)CH2CH2C(O)OH}2(cis-1,4-DACH)] (3) was accompanied by reduction to 1. It was found that solvolysis of 2 and formation of a μ-oxo dinuclear species (5) is the key step. The dinuclear species can then undergo reduction to a 1:1 mixture of 1 and 2 with concomitant elimination of oxygen (1/2 O2 in the form of H2O2). The whole process is fostered by heat and/or light, which could favor solvolysis of 2 as well as decomposition of hydrogen peroxide to water and oxygen so preventing the reoxidation of 1 to 2. Because of its peculiar behavior, compound 5 could be exploited also for the development of a technology for water splitting.

Most evidence indicates that platinum(IV) prodrugs are rapidly reduced under physiological conditions by biologically relevant reducing agents, such as ascorbic acid and glutathione; however, the precise mechanisms of reduction are not fully understood, thus preventing rational design of compounds with better pharmacological properties. In the present study, reduction of three all-trans platinum(IV) compounds of formula [PtCl(2)(CH(3)COO)(2)LL'] (LL' = {E-HN═C(CH(3))OCH(3)}(2), 1c, (H(3)N)(cyclohexylamine), 2c, and (H(3)N)(1-adamantylamine), 3c) by two biologically relevant reductants (ascorbic acid and glutathione) and by a classical coordination chemistry reductant (triphenylphosphine) has been investigated. Reduction by triphenylphosphine and glutathione leads, in all cases examined, to loss of the two chlorides and formation of the diacetato species trans-[Pt(CH(3)COO)(2)LL']. This is in accord with an "inner-sphere" redox process in which a chlorido ligand bridges the reductant with the platinum(IV) center. In contrast, reduction by ascorbic acid/sodium ascorbate 1:1 leads, in addition to the diacetato complex, also to formation of a significant amount of dichlorido species, particularly in the case of 1c (31%) and to a lesser extent of 3c (16%). The latter results indicate that ascorbic acid is less efficient to promote an inner-sphere redox process (attack on a chlorido ligand), therefore allowing participation of an "outer-sphere" mechanism, ultimately leading to formation of the more stable dichlorido species. The dependence of the yield of diacetato species upon the steric hindrance of the carrier ligand (69%, 84%, and 95% for 1c, 3c, and 2c, respectively) points to the possible participation of a second type of inner-sphere mechanism in which the interaction between the ascorbate and a chlorido ligand of the platinum(IV) substrate is mediated by a platinum(II) catalyst, the transition state resembling that of a platinum(II)-catalyzed ligand substitution at a platinum(IV) center. This investigation demonstrates that different species can be obtained by reduction of a platinum(IV) prodrug (depending upon the configuration of the substrate and the nature of the intervening reducing agent) and can explain some lack of correlation between prodrug and putative active species as well as contrasting literature results.

Platinum anticancer drug binding to DNA creates large distortions in the cross-link (G*G*) and the adjacent XG* base pair (bp) steps (G* = N7-platinated G). These distortions, which are responsible for anticancer activity, depend on features of the duplex (e.g., base pairing) and of the cross-link moiety (e.g., the position and canting of the G* bases). The duplex structure stabilizes the head-to-head (HH) over the head-to-tail (HT) orientation and right-handed (R) over left-handed (L) canting of the G* bases. To provide fundamental chemical information relevant to the assessment of such duplex effects, we examine (S,R,R,S)-BipPt(oligo) adducts (Bip = 2,2'-bipiperidine with S,R,R,S chiral centers at the N, C, C, and N chelate ring atoms, respectively; oligo = d(G*pG*) with 3'- and/or 5'-substituents). The moderately bulky (S,R,R,S)-Bip ligand favors L canting and slows rotation about the Pt-G* bonds, and the (S,R,R,S)-BipPt(oligo) models provide more useful data than do dynamic models derived from active Pt drugs. All 5'-substituents in (S,R,R,S)-BipPt(oligo) adducts favor the normal HH conformer (∼97%) by destabilizing the HT conformer through clashes with the 3'-G* residue rather than through favorable H-bonding interactions with the carrier ligand in the HH conformer. For all (S,R,R,S)-BipPt(oligo) adducts, the S pucker of the 5'-X residue is retained. For these adducts, a 5'-substituent had only modest effects on the degree of L canting for the (S,R,R,S)-BipPt(oligo) HH conformer. This small flanking 5'-substituent effect on an L-canted HH conformer contrasts with the significant decrease in the degree of R canting previously observed for flanking 5'-substituents in the R-canted (R,S,S,R)-BipPt(oligo) analogues. The present data support our earlier hypothesis that the distortion distinctive to the XG* bp step (S to N pucker change and movement of the X residue) is required for normal stacking and X·X' WC H bonding and to prevent XG* residue clashes.

Increasing evidence indicates that sulfur-containing molecules can play important roles in the activity of platinum anticancer drugs. Although nuclear DNA is retained to be the ultimate target, these platinum compounds can readily react with a variety of other substrates containing a soft donor atom, such as proteins, peptides, and low molecular weight biomolecules, before reaching DNA. In a recent study it was demonstrated that the DNA platination rate of a trans-geometry antitumor drug was dramatically enhanced by methionine binding, thus suggesting that the thioether could serve as a catalyst for DNA platination. In this work we performed detailed studies on the reactions of a widely investigated and very promising trans-platinum complex having two iminoethers and two chlorido ligands, trans-EE, with methionine (Met) and guanosine 5'-monophosphate (GMP). The results show that in the reaction of trans-EE with methionine the bisadduct is the dominant species in the early stage of the reaction. The reaction is also influenced by chloride concentration: at low NaCl the bis-methionine adduct is formed in preference, whereas the monoadduct is favored at high NaCl concentration. Not only the monomethionine complex, trans-PtCl(E-iminoether)(2)(AcMet), but also the bis-methionine adduct, trans-Pt(E-iminoether)(2)(AcMet)(2), which has already lost both leaving chlorides, can react with GMP to form the ternary platinum complex trans-Pt(E-iminoether)(2)(AcMet)(GMP). The latter reaction discloses the possibility of direct coordination to DNA of a platinum-protein adduct, in which the two carrier ligands remain intact; this is not the case of cis-oriented platinum complexes, like cisplatin, for which formation of a ternary complex is usually accompanied by loss of at least one carrier ligand. Interestingly, isomerization from S to N coordination of one methionine takes place in the bis-methionine complex at neutral pH, while the monoadduct appears to be stable. The shift from S to N coordination of one methionine in the trans-bis-methionine adduct can easily account for the obtainment of the cis isomer in the bis-chelated Pt(Met-S,N)(2) end product.

The highly distorted Pt(d(G*pG*)) (G* = N7-platinated G) 17-membered macrocyclic ring formed by cisplatin anticancer drug binding to DNA alters the structure of the G*G* base pair steps, canting one base, and increases dynamic motion, complicating solution structural studies. However, the ring appears to favor the HH1 conformation (HH1 denotes head-to-head guanine bases, 1 denotes the normal direction of backbone propagation). Compared to cisplatin, analogues with NH groups in the carrier ligand replaced by bulky N-alkyl groups are more toxic and less active and form less dynamic adducts. To examine the molecular origins for the biological effects of steric bulk, we evaluate Me(4)DABPt(d(G*pG*)) models; the bulk and chirality of Me(4)DAB (N,N,N',N'-tetramethyl-2,3-diaminobutane with S,S or R,R configurations at the chelate ring carbons) impede dynamic motion and enhance the utility of NMR methods for identifying and characterizing conformers. Unlike past studies of adducts with such bulky carrier ligands, in which no HH conformer was found, the Me(4)DABPt(d(G*pG*)) adducts did form the HH1 conformer, providing compelling evidence that the sugar-phosphate backbone can impose constraints sufficient to overcome the alkyl-group steric effects. The HH1 conformer exhibits no significant canting. The (S,S)-Me(4)DABPt(d(G*pG*)) adduct has the least amount of the "normal" HH1 conformer and the greatest amount of the ΔHT1 conformer (ΔHT1 = head-to-tail G* bases with Δ chirality) ever observed (88% under some conditions). Thus, our results lead us to hypothesize that the low activity and high toxicity of analogues of cisplatin having carrier ligands with N-alkyl groups arise from the low abundance and minimal canting of the HH1 conformer and possibly from the adverse effects of an abundant ΔHT1 conformer. The new findings advance our understanding of the chemistry of the Pt(d(G*pG*)) macrocyclic ring and of the effects of carrier-ligand steric bulk on the properties of the ring.

The X-ray structural and NMR characterization of a bis-guanine derivative of a cisplatin analogue designed to reduce the rate of the Pt-N7 rotation of the coordinated guanine nucleobases by more than 1-million-fold is reported. The [Pt{(+/-)-Me(2)dab}(9-EtG)(2)](NO(3))(2) (Me(2)dab = N,N'-dimethyl-2,3-diaminobutane, 9-EtG = 9-ethyl-guanine) complex crystallizes in the P2(1)/n space group, and the crystal contains a racemic mixture of complex molecules. The data were collected at 120 +/- 2 K, and the crystal and molecular structure (comprising one disordered nitrate) were resolved and refined to conventional agreement factors of R1 = 0.0270 and wR2 = 0.0565. The guanine ligands assume the less common head-to-head (HH) orientation, disclosing full details of the intramolecular relationships between cis guanines and between guanine and cis amine. Moreover, an understanding has been gained of the steric factors determining induction of asymmetry (from carbons to adjacent nitrogen atoms) and puckering of the chelate ring (delta or lambda for R,S,S,R or S,R,R,S configurations at the N,C,C,N chelate-ring atoms, respectively) within the Me(2)dab ligand. The chemical shift separation between H8 signals of the two HT atropisomers and between the two H8 signals of the single HH atropisomer can be explained in terms of canting of the nucleobases relative to the coordination plane and in terms of the different relationships between the H8 proton of one guanine and the shielding zone of the cis guanine. Furthermore, for each configuration of the Me(2)dab ligand (R,S,S,R or S,R,R,S), the NMR data indicate that the handedness of canting is similar for the two guanines in all three (two HT and one HH) conformers (R canting for R,S,S,R and L canting for S,R,R,S configuration).

Me(4)DABPtG(2) adducts with the bulky C(2)-symmetric chiral diamine, Me(4)DAB (N,N,N',N'-tetramethyl-2,3-diaminobutane with R,R and S,S configurations at the chelate ring C atom, G = guanine derivative), exhibit slow conformer interchange and are amenable to characterization by NMR methods. The investigation of the cis-PtA(2)G(2) adducts formed by clinically widely used anticancer drugs [A(2) = diaminocyclohexane, (NH(3))(2)] is impeded by the rapid conformer interchange permitted by the low A(2) bulk near the inner coordination sphere. Me(4)DABPtG(2) adducts exist as a mixture of exclusively head-to-tail (HT) conformers. No head-to-head (HH) conformer was observed. The Me(4)DAB chirality significantly influences which HT chirality is favored (DeltaHT for S,S and LambdaHT for R,R). For simple G ligands, the ratio of favored HT conformer to less favored HT conformer is approximately 2:1. For guanosine monophosphate (GMP) ligands, the phosphate group cis G N1H hydrogen bonding favors the LambdaHT and the DeltaHT conformers for 5'-GMP and 3'-GMP adducts, respectively. For both HT conformers of cis-PtA(2)G(2) adducts, the G nucleobase plane normally cants with respect to the coordination plane in the same direction, left or right, for a given A(2) chirality. In contrast, the results for Me(4)DABPtG(2) adducts provide the first examples of a change in the canting direction between the two HT conformers; this unusual behavior is attributed to the fact that canting always gives long G O6 to N-Me distances and that these Me(4)DAB ligands have bulk both above and below the coordination plane. These results and ongoing preliminary studies of Me(4)DABPt adducts with G residues linked by a phosphodiester backbone, which normally favors HH conformers, all indicate that a high percentage of HT conformer is present. Collectively, these findings advance fundamental concepts in Pt-DNA chemistry and may eventually help define the role of the carrier-ligand steric effects on anticancer activity.

Platinum bis-amidine complexes (both the cis and trans isomers) are stable in acetone and chlorinated solvents but are unstable in protic solvents such as methanol or water. In the latter solvents an initial cis/trans isomerization leads to formation of an equilibrium mixture with a cis/trans ratio of about 1:4; subsequently a dinuclear platinum(III) complex (1) is formed under aerobic conditions while, under anaerobic conditions, a trinuclear platinum(II) compound (2) is obtained. We hypothesize that the process of isomerization and formation of polynuclear compounds (1 and 2) have a common precursor: a dinuclear platinum(II) species supported by two bridging amidinato ligands (3), formed in small yield, which can either dissociate back to monomers of cis/trans configuration or evolve in two different polynuclear species depending upon the aerobic/anaerobic conditions. In aerobic conditions, oxidation of platinum(II) to platinum(III) together with formation of two additional amidinato bridges across the two platinum centers takes place leading to compound 1. In contrast, in anaerobic conditions, oxidation of platinum is prevented and the dinuclear platinum(II) precursor remains in solution until it reacts with an extra molecule of the starting mononuclear complex which loses its two amidine ligands and cross-links the two bridging amidinato ligands of 3 to yield compound 2. This latter features two triply bridging amidinato ligands linking the three platinum units to form a pocket. Complexes 1 and 2 have been characterized by means of IR and NMR spectroscopy, mass spectrometry, elemental analysis, and X-ray crystallography.

The synthesis and the NMR and X-ray structural characterization of a cisplatin analogue designed to reduce the Pt-N7 rotation of a coordinated guanine base by a billion times are reported. The [Pt(dmm){(+/-)-bip}] (dmm=dimethylmalonato; bip=2,2'-bipiperidine) complex crystallizes in the C2/m space group, which contemplates a mirror plane bisecting the bip and dmm ligands. Because the bip moiety (R, R or S, S configuration at the 2,2'-carbon atoms) does not have planes of symmetry, the requirements of the crystal symmetry are satisfied by a statistical disorder made of bip molecules of R, R or S, S configurations alternating at the same crystallographic site. Such an unexpected arrangement has been permitted by a "quasi planarity" of the bip ligand [maximum deviation from the mean plane through the C and N atoms of 0.2927(9) A], which allows bip molecules of different chiralities to fit in the same space. The bip array of heavy atoms is overlaid, from both sides, by a layer of "quasi axial" (C)H and (N)H atoms (six per side). Those on one side are hydrogen-bonded to the dmm oxygen atoms of another complex molecule joined in a pair. The distance between the average platinum coordination planes is as short as 3.498(1) A, comparable to those found in crystals of the [PtCl 2(bipy)] complex (bipy=2,2'-bipyridine) and of graphite, in which, however, all atoms of each unit are rigorously coplanar and there are no out-of-plane hydrogen atoms. The NMR data show a net chemical shift separation between geminal methylene protons, with the "quasi axial" protons being always at higher field with respect to the "quasi equatorial" ones. This is in accordance with a rigid bip ligand frame and the inability of the bip methylene protons adjacent to the coordinated nitrogen to rotate away from a cis-G base (G=guanine) during G rotation around the Pt-N7 bond.

In [PtCl2(cis-1,4-DACH)] (DACH = diaminocyclohexane), the N-Pt-N bite angle (> or =97 degrees , as determined by X-ray diffraction analysis) is much larger than those found in other Pt complexes with bidentate diamines or in cisplatin (approximately 91 degrees ). Hence, the possibility exists that in (cis-1,4-DACH)PtG 2 adducts, rotation of the G's around the Pt-N7 bonds is slowed enough to allow observation of different conformers. In accord with this prevision, decreasing the temperature to 238 K enabled us to observe different conformers of (cis-1,4-DACH)Pt(5'-GMP) 2 (GMP = guanosine monophosphate). This observation is the first case in which such conformers for a platinum derivative with primary diamines and untethered guanines have been resolved and represents the closest model to clinically effective cisplatin obtained to date. We also found that the presence of the 1,4-DACH ligand increased the intensity of the circular dichroism signal stemming from the dominance of an HT conformer (DeltaHT in the adduct with 3'-GMPs and LambdaHT in the adduct with 5'-GMPs).

Complexes of the type syn-(R,S)-Me(3)dienPtL (Me(3)dien = N,N',N' '-trimethyldiethylenetriamine; L = guanine or hypoxanthine derivative) have two rotamers, a feature useful for assessing hydrogen-bond interactions between a Me(3)dien NH group and either the O6 or the phosphate group of the coordinated L. The two rotamers are defined as endo and exo for the rotamer with the six-membered ring of the purine on the same side and on the opposite side, respectively, of the coordination plane as the N-Me's. For L = 5'-GMP and 5'-IMP the endo rotamer is the exclusive form (at neutral and basic pH) or is present at 90% and more (low pH where 5'-phosphate group is protonated). A 5'-phosphate group can be positioned to form a direct H-bond with a Me(3)dien NH group only in the endo form; such an H-bond explains this high endo preference. Such a direct phosphate-NH H-bond is not possible for other complexes used in this study because either L has no phosphate group (9-EtG, Guo) or the phosphate is at the 3'-position (3'-GMP and 3'-IMP), too far for H-bonding. Nevertheless, a preference for the endo rotamer was observed for these L also. This result is opposite to that expected both from potential steric repulsion of the L O6 with the N-Me groups and also from the lack of a potential favorable H-bond interaction between L O6 and a Me(3)dien NH. For the 9-EtG adduct, the temperature dependence of the endo/exo equilibrium and the activation parameters for endo/exo interconversion suggest that the preference for the endo rotamer arises from the hydration of the Me(3)dien NH groups; such hydration is favorable in the endo rotamer. At basic pH, N1H deprotonation increases the H-bond capacity of O6, and the exo rotamer increases in stability, becoming the dominant rotamer for the 9-EtG and Guo adducts. For L = 3'-GMP and 3'-IMP, stabilization of the endo form upon phosphate deprotonation at neutral pH was observed. This result is attributed to an H-bonding network involving water, the 3'-phosphate, and the Me(3)dien NH groups.

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.

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.

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.

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.

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.

Cisplatin forms the cis-Pt(NH3)2(d(GpG)) cross-link with DNA. We have recently created novel d(GpG) conformations by using "retro models" (complexes having bulky carrier ligands designed to slow d(GpG) dynamic motion). Our results define four conformer classes: HH1, HH2, delta HT1, and delta HT2, with a head-to-head or head-to-tail base orientation and a phosphodiester backbone with a normal (1) or opposite (2) propagation direction. Moreover, each G residue can be syn or anti, and the base canting can be left-handed (L) or right-handed (R). Thus, 32 variants of cis-Pt(NH3)2(d(GpG)) are conceivable, but the adduct is too dynamic to study. Thus far, by using retro models, we have obtained evidence for five variants with d(GpG) but only four with GpG. We therefore selected Me2DAPPt(GpG) complexes for study by 1H and 31P NMR spectroscopy, CD spectroscopy, and molecular mechanics and dynamics (MMD) calculations. Coordinated Me2DAP (N,N'-dimethyl-2,4-diaminopentane) has N, C, C, N chiral centers designated, for example, as R,R,R,R. This ligand has greater flexibility and more readily inverted N centers than ligands used previously in GpG retro models. One goal was to determine whether the GpG ligand can control the configuration of a carrier ligand. (R,R,R,R)-Me2DAPPt(GpG) forms the anti, anti HH1 R variant almost exclusively. Equal populations of the two possible linkage isomers of (S,R,R,R)-Me2DAPPt(GpG) are formed, both favoring the anti, anti HH1 R, variant; however, the isomer with the 5'-G cis to the S nitrogen has sharper signals, suggesting that interligand interactions are more favorable. Indeed, this linkage isomer was the major product of isomerization when (R,R,R,R)-Me2DAPPt(GpG) was kept at pH approximately 9.5 to allow N center equilibration. Steric clashes between the Me2DAP C-Me groups and the G O6 atoms found by MMD calculations appear to disfavor the HH1 conformer of (S,S,S,S)-Me2DAPPt(GpG) and (S,S,S,R)-Me2DAPPt(GpG) complexes. These two complexes have a significant population of the anti, syn delta HT1 conformer, as indicated by broad 1H NMR signals and by 31P NMR and CD data. Equilibration of (S,S,S,R)-Me2DAPPt(GpG) at pH 9.5 leads to a mixture of (S,S,S,S)-Me2DAPPt(GpG) and at least one isomer of (S,S,S,R)-Me2DAPPt(GpG). Thus, second-sphere communication (hydrogen bonding and steric interligand interactions) influences both GpG conformation and Me2DAP configuration.

Coordinated N,N',N"-trimethyldiethylenetriamine (Me3dien) has several possible configurations: two have mirror symmetry (R,S configurations at the terminal nitrogens) and the terminal N-Me's anti or syn with respect to the central N-Me (anti-(R,S) and syn-(R,S) isomers, respectively), and two are nonsymmetrical (R,R and S,S configurations at terminal nitrogens, rac denotes a 1:1 mixture of the two isomers). For each configuration, two Me3dienPtG atropisomers can be formed (anti or syn orientation of central N-Me and G 06, G = guanine derivative), and these can be observed since the terminal N-Me's decrease the rate of G rotation about the Pt-N7 bond. In symmetrical syn-(R,S)-Me3dienPtG derivatives with G = 9-EtG and 3'-GMP, the anti rotamer, which can form O6-NH H-bonds, was slightly favored over the syn rotamer but never more than 2:1. This anti rotamer is also favored by lower steric repulsion between the terminal N-Me's and G O6; thus, the contribution of O6-NH H-bonding to the stability of the anti rotamer could be rather small. With G = 5'-GMP, an O6-NH H-bond in the anti rotamer and a phosphate-NH H-bond in the syn rotamer can form. Only the syn rotamer was detected in solution, indicating that NH H-bonds to 5'-phosphate are far more important than to O6, particularly since steric factors favor the anti rotamer. Interconversion between rotamers was faster for syn-(R,S)- than for rac-Me3dien derivatives. This appears to be determined by a smaller steric impediment to G rotation of two "quasi equatorial" N-Me's, both on one side of the platinum coordination plane (syn-(R,S) isomer), than one "quasi equatorial" and one "quasi axial" N-Me on either side of the coordination plane (rac isomer).

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.

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.

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.

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.

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.

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.

The antitumor drugs 1-nitro-9-[(2-(dialkylamino)ethyl)amino]acridines (alkyl = Me, A(1); Et, A(2)) with platinum(II) give tridentate coordination compounds in which the two nitrogens of the ethylenediamine side chain and the C(8) carbon atom of the acridine ring system act as donor atoms. An excess of triphenylphosphine displaces the residual chloride coordinated to platinum but leaves unaltered the tridentate acridine ligand. The structures of [Pt(A(1)-H)Cl], 1, and [Pt(A(1)-H)(PPh(3))]Cl, 3, have been solved by single-crystal X-ray diffraction. 1.CHCl(3) crystallizes in the orthorhombic system, space group P2(1)2(1)2(1) (no. 19), with a = 8.715(1) Å, b = 11.045(2) Å, c = 22.609(4) Å, Z = 4, R = 0.0559, and R(w) = 0.0561 for 1502 reflections with F > 3sigma(F). 3.(1)/(2)CH(2)Cl(2) crystallizes in the monoclinic system, space group P2(1)/c (no. 14), with a = 13.418(3) Å, b = 14.053(3) Å, c = 18.918(4) Å, beta = 97.21(3) degrees, Z = 4, R = 0.0591, and R(w) = 0.0611 for 3608 reflections with F > 4sigma(F). In both complexes the acridine ligand adopts an imino-type configuration with the proton of the exocyclic 9-amino group shifted on N(10). Because of a severe steric interaction between the nitro group in the 1-position and the chelate diamine chain in the 9-position, the acridine moiety is folded about the C(9)-N(10) vector with an average angle between outer rings of 12 degrees. Moreover, the acridine aromatic moiety and the platinum coordination planes are twisted, forming a dihedral angle of ca. 20 degrees. The steric repulsion between the nitro and the diamine groups appears to provide the driving force to metalation. The H(10) proton has a great tendency to be engaged in H-bonding as shown by X-ray and solution studies. The formation of a H-bond with a rather poor acceptor such as the chloride ion can cause a downfield shift of the H-resonance as large as 6 ppm.