The crystal structures of three porphyrin diacid species, [H 4 OEP](ClO 4 ) 2 , [H 4 TPP](ClO 4 ) 2 , and [H 4 TMP]-(ClO 4 ) 2 , have been determined from low-temperature X-ray diffraction data to delineate how the peripheral substituents of the porphyrin affect the overall molecular flexibility. [H 4 OEP](ClO 4 ) 2 (|C b | ) 0.46 Å), [H 4 TMP](ClO 4 ) 2 (|C b | ) 0.67 Å, molecule 1), and [H 4 TPP](ClO 4 ) 2 (|C b | ) 0.93 Å) show increasingly saddled core conformations with effective D 2d symmetry. The mean porphyrin-aryl group dihedral angles in [H 4 TPP](ClO 4 ) 2 and [H 4 TMP](ClO 4 ) 2 (molecule 1) are 27(2)°and 63(13)°, respectively. The steric bulk of the mesityl substituents in [H 4 TMP] 2+ limits the range of observed porphyrin-aryl group dihedral angles to >50°and, consequently, the magnitude of the core distortion. [H 4 TMP] 2+ is therefore less flexible than [H 4 TPP] 2+ . Molecular mechanics calculations, using a modified version of MM2 (87) and a newly developed force field for porphyrin diacids, correctly predict that the flexibility of mesotetraaryl porphyrin diacids decreases as the steric bulk of the peripheral substituentsrelated minima with D 2d -saddled and C 2h -stepped core conformations. The in Vacuo strain energy barrier to inversion of the lowest-energy D 2d -saddled conformation increases from 0.45 kcal/mol in [H 4 porphine] 2+ to 1.9 kcal/mol in [H 4 T-2,6-Cl 2 PP] 2+ . The calculations indicate that the relative stability and magnitude of distortion of the D 2d isomer increases as the steric bulk of the peripheral substituents increases; [H 4 OEP] 2+ is therefore calculated to be less distorted than [H 4 TPP] 2+ , in agreement with the X-ray structures of these species.

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An improved method for the preparation of the heme octapeptide acetyl-MP8, obtained by proteolysis of horse heart cytochrome c, is described. AcMP8 obeys Beer's law at pH 7.0 in aqueous solution up to a concentration of 3 x 10(-)(5) M. The self-association constant measured at 25 degrees C (log K(D) = 4.04) is an order of magnitude lower than that for MP8, reflecting the role of the N-acetyl protecting group in abolishing intermolecular coordination. However, AcMP8 does form pi-stacked dimers in aqueous solution with increasing ionic strength. A more weakly packed pi-pi dimer reaches a maximum abundance at approximately 3 M ionic strength, but a more tightly packed dimer is favored at &mgr; > 3 M. An equilibrium model based on charge neutralization by specific binding of Na(+) ions gives a total molecular charge of 3- for AcMP8 at pH 7.0 and a self-association constant log K(D) = 4.20. AcMP8 exhibits six spectroscopically active pH-dependent transitions. The Glu-21 c-terminal carboxylate binds to the heme iron at low pH (pK(a) = 2.1) but is substituted by His-18 (pK(a) = 3.12) as the pH increases. The two heme propanoic acid substituents ionize with pK(a)'s of 4.95 and 6.1. This is followed by ionization of iron-bound water with a pK(a) = 9.59, DeltaH = 48 +/- 1 kJ mol(-)(1), and DeltaS = -22 +/- 3 J K(-)(1) mol(-)(1). The electronic spectra indicate that AcMP8 is predominantly in the S = (5)/(2) state at pH 7.0, while the hydroxo complex at pH 10.5 corresponds to an equilibrium mixture of S = (5)/(2) and S = (1)/(2) states at 25 degrees C. In the final transition, His-18 ionizes to form the S = (1)/(2) histidinate complex with a pK(a) of 12.71. AcMP8 is relatively stable under alkaline conditions, dimerizing slowly at high pH (k = 2.59 +/- 0.14 M(-)(1) s(-)(1)) to form a high-spin &mgr;-oxo-bridged species. The pH-dependent behavior of AcMP8 in the presence of excess 3-cyanopyridine, however, is markedly different. At low pH, AcMP8 simultaneously binds the exogenous ligand and the Glu-21 c-terminal carboxylate with a pK(a) < 2. His-18 replaces the carboxylate ligand at higher pH (pK(a) = 2.60), and both heme propanoic acid groups ionize with a mean pK(a) = 5.10. Unlike AcMP8.OH(-), the axial histidine of the 3-CNPy complex ionizes at near neutral pH (pK(a) = 7.83), prior to being replaced by OH(-) (pK(a) = 10.13). The sixth transition in the AcMP8/3-CNPy system produces the bis(hydroxo) complex (pK(a) > 13).

pi-Acceptor effects are often used to account for the unusual high lability of [Pt(terpy)L]((2)(-)(n)+) (terpy = 2,2':6',2' '-terpyridine) complexes. To gain further insight into this phenomenon, the pi-acceptor effect was varied systematically by studying the lability of [Pt(diethylenetriamine)OH(2)](2+) (aaa), [Pt(2,6-bis-aminomethylpyridine)OH(2)](2+) (apa), [Pt(N-(pyridyl-2-methyl)-1,2-diamino-ethane)OH(2)](2+) (aap), [Pt(bis(2-pyridylmethyl)amine)OH(2)](2+) (pap), [Pt(2,2'-bipyridine)(NH(3))(OH(2))](2+) (app), and [Pt(terpy)OH(2)](2+) (ppp). The crystal structure of the apa precursor [Pt(2,6-bis-aminomethylpyridine)Cl]Cl.H(2)O was determined. The substitution of water by a series of nucleophiles, viz. thiourea, N,N-dimethylthiourea, N,N,N',N'-tetramethylthiourea, I(-), and SCN(-), was studied under pseudo-first-order conditions as a function of concentration, pH, temperature, and pressure, using stopped-flow techniques. The data enable an overall comparison of the substitution behavior of these complexes, emphasizing the role played by the kinetic cis and trans pi-acceptor effects. The results indicate that the cis pi-acceptor effect is larger than the trans pi-acceptor effect, and that the pi-acceptor effects are multiplicative. DFT calculations at the B3LYP/LACVP level of theory show that, by the addition of pi-acceptor ligands to the metal, the positive charge on the metal center increases, and the energy separation of the frontier molecular orbitals (E(LUMO) - E(HOMO)) of the ground state Pt(II) complexes decreases. The calculations collectively support the experimentally observed additional increase in reactivity when two pi-accepting rings are adjacent to each other (app and ppp), which is ascribed to "electronic communication" between the pyridine rings. The results furthermore indicate that the pK(a) value of the platinum bound water molecule is controlled by the pi-accepting nature of the chelate system and reflects the electron density around the metal center. This in turn controls the rate of the associative substitution reaction and was analyzed using the Hammett equation.

The preparation and characterization of two crystalline forms of [Fe(TMP)(5-MeHIm)2]ClO4 with distinctly different molecular structures are reported. Crystal structure analysis shows that paral-[Fe(TMP)(5-MeHIm)2]ClO4 has the axial imidazole ligands arranged in a relative parallel orientation (over a slightly S 4-ruffled porphyrin core) and perp-[Fe(TMP)(5-MeHIm)2]ClO4 has the axial imidazole ligands arranged in a relative perpendicular orientation (over a considerably S 4-ruffled porphyrin core). The two species have different Mössbauer and solid-state EPR spectra. The small quadrupole splitting (ΔE q = 1.78(1) mm/s, 120 K) and a single observable EPR g max value (3.43 at 4.2 K) for perp-[Fe(TMP)(5-MeHIm)2]ClO4 are indicative of the relative perpendicular arrangement of the axial ligands. The larger quadrupole splitting (ΔE q = 2.557(3) mm/s, 120 K) and rhombic g-tensor (g 1 = 2.69, g 2 = 2.34−2.43, and g 3 = 1.75) in the solid state and in frozen DMF−acetonitrile 3:1 (g 1 = 2.64, g 2 = 2.30, and g 3 =1.80) at 4.2 K for paral-[Fe(TMP)(5-MeHIm)2]ClO4 are indicative of a relative parallel axial ligand orientation. The actual axial ligand dihedral angles are Δφ = 76° and Δφ = 26 or 30° for perp- and paral-[Fe(TMP)(5-MeHIm)2]ClO4, respectively, and thus the dihedral angle at which the EPR spectral type changes from large g max to rhombic must be 30 < Δφ < 76°. Because the porphyrin and axial ligands are similar for both crystalline forms of [Fe(TMP)(5-MeHIm)2]ClO4, a more direct correlation between molecular and electronic structure has been established. Molecular mechanics calculations indicate that nonbonded interactions between the axial ligands and meso-mesityl groups of [Fe(TMP)(5-MeHIm)2]+ destabilize a relative parallel orientation for the axial ligands, yet the parallel orientation is observed in all frozen solution samples as confirmed by EPR investigations. This is believed to be due to the competing stabilization of the electronic state of the rhombically distorted parallel complex with an energy stabilization of 2.8−3.7 kcal/mol, as compared to the energy destabilization of 2.6 kcal/mol obtained from MM calculations.

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The reaction of BF(3).OEt(2) with the bis(nitro) complex of iron(III) picket-fence porphyrin, [K(18C6)(OH(2))][Fe(TpivPP)(NO(2))(2)], leads to the formation of a transient porphyrin intermediate, assigned on the basis of its rhombic low-spin EPR spectrum as the five-coordinate N-bound mono(nitro) iron(III) derivative, [Fe(TpivPP)(NO(2))]. This species is reactive and readily undergoes oxygen atom transfer to form [Fe(III)(TpivPP)(NO(3))] and [Fe(II)(TpivPP)(NO)]. The reactions have been followed by EPR and IR spectroscopy. [Fe(TpivPP)(NO(2))] has a rhombic EPR spectrum (g = 2.60, 2.35, and 1.75) in chlorobenzene and CH(2)Cl(2) and is spectroscopically distinct from the bis(nitro) starting material (g = 2.70, 2.50, and 1.57). Oxidation of the nitrosyl species to [Fe(TpivPP)(NO(3))] proceeds via an intermediate assigned as [Fe(TpivPP)(NO(2))] on the basis of its EPR spectrum. The crystal structure of one of the reaction products, [Fe(TpivPP)(NO(3))], has been determined. The nitrate ion of [Fe(TpivPP)(NO(3))] is bound to the iron(III) ion in a "symmetric" bidentate fashion within the ligand-binding pocket of the porphyrin pickets. Individual Fe-O distances are 2.123(3) and 2.226(3) Å. The dihedral angle between the plane of the nitrate ion and the closest N(p)-Fe-N(p) plane is 10.0 degrees. The Fe-N(p) bonds (and trans N(p)-Fe-N(p) angles) perpendicular and parallel to the plane of the axial ligand average to 2.060(5) Å (154.84(9) degrees ) and 2.083(3) Å (146.14(9) degrees ), respectively. Crystal data for [Fe(TpivPP)(NO(3))]: a = 23.530(2) Å, b = 10.0822(5) Å, c = 48.748(3) Å, beta = 92.145(5) degrees, monoclinic, space group I2/a, V = 11556.4(14) Å(3), Z = 8, FeN(9)O(7)C(64)H(64), 8798 observed data, R(1) = 0.0606, wR(2) = 0.1313, all observations at 127(2) K.

Topoisomerase IB (Top1) is a key eukaryotic nuclear enzyme that regulates the topology of DNA during replication and gene transcription. Anticancer drugs that block Top1 are either well-characterized interfacial poisons or lesser-known catalytic inhibitor compounds. Here we describe a new class of cytotoxic redox-stable cationic Au3+ macrocycles which, through hierarchical cluster analysis of cytotoxicity data for the lead compound, 3, were identified as either poisons or inhibitors of Top1. Two pivotal enzyme inhibition assays prove that the compounds are true catalytic inhibitors of Top1. Inhibition of human topoisomerase IIα (Top2α) by 3 was 2 orders of magnitude weaker than its inhibition of Top1, confirming that 3 is a type I-specific catalytic inhibitor. Importantly, Au3+ is essential for both DNA intercalation and enzyme inhibition. Macromolecular simulations show that 3 intercalates directly at the 5′-TA-3′ dinucleotide sequence targeted by Top1 via crucial electrostatic interactions, which include π–π stacking and an Au···O contact involving a thymine carbonyl group, resolving the ambiguity of conventional (drug binds protein) vs unconventional (drug binds substrate) catalytic inhibition of the enzyme. Surface plasmon resonance studies confirm the molecular mechanism of action elucidated by the simulations.