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)PtG₂with CCC =N,N‘-Dimethyl-2,3-diaminobutane

Abstract

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.

The First Pure ΛHT Rotamer of a Complex with a cis‐[Metal(nucleotide)2] Unit: A cis‐[Pt(amine)2(nucleotide)2] ΛHT Rotamer with Unique Molecular Structural Features

“…Common CD features of previously studied cis-[PtA 2 G 2 ] adducts (G = detached guanine-base derivatives) allowed us to establish that the HT conformers make the greatest contribution to the CD spectrum [54,57,59,60] and that HT conformers of opposite chirality (L or D) also have opposite CD features. Moreover, the CD spectrum of a mixture of conformers is reflective of the dominant conformer in solution.…”

Slowly Exchanging cis‐PtA2B2 Atropisomers with A2 = Chiral Diamine Ligands and B = 5,6‐Dimethylbenzimidazole

“…[11,12,16,17] This dominance was attributed to interligand interactions, which were classified as "first-to-first," "first-to-second," and "second-to-second" sphere com- munications. [17,18] The latter two types of interactions involve phosphate groups, [11,12,17,18] and in this study we examine adducts lacking this group in order to focus on firstto-first sphere communications (FFC). FFC are interligand interactions involving portions of the ligands close to the metal center.…”

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 HaveR,RandS,SConfigurations at the Asymmetric Diamine

“…[9,14,15] Studies with [Pt{(S,R,R,S)-Me 2 dab}G 2 ] and [Pt{(R,S,S,R)-Me 2 dab}G 2 ] complexes (Me 2 DAB = N,N'-dimethyl-2,3-diaminobutane, and has four asymmetric centers at the N, C, C, and N chelate ring atoms) demonstrated a correlation between the sign of the CD signal and the chirality of the major HT form. [14,15] HT conformers have a head-to-tail orientation of the guanine bases and can have either a D or L chirality depending upon the handedness of two straight lines; one passes through the platinum center perpendicularly to the coordination plane, and the other connects the O6 atoms of the two guanines. [16,17] Furthermore, studies with the related [Pt{(S,R,R,S)-bip}G 2 ] and [Pt{(R,S,S,R)-bip}G 2 ] complexes (BIP = 2,2'-bipiperidine) indicated that a mixture of 25 % DHT, 50 % HH, and 25 % LHT essentially had a CD spectrum that lacked any intensity.…”