The theoretical prediction power of the software package QikProp was tested. This was achieved by comparing experimentally known results to predicted values. First, simple molecular descriptors for physicochemical properties: octanol -water partition (log P), water solubility (log S), dipole moment, Ionisation Potential (IP) and Electron Affinity (EA) were compared to their experimentally determined counterparts. For all of the descriptors, except EA, a relatively good linear correlation was obtained. Experimentally derived EA values are relatively scarce and often quite inconsistent, which made it difficult to construct a reliable test collection. When compared to values calculated by the Density Functional Theory (DFT) method a reasonable correlation was observed but there is much room for improvement. A clear Gaussian distribution pattern was obtained when a collection of $ 470 marketed orally bioavailable drug compounds was used to generate the physicochemical properties investigated. The idea was explored whether the prediction power of ADME modules could be tested in a qualitative way, based on broad assumptions, using different classes of marketed drug compounds. It was found that this approach gives one a good idea about which modules deserve further attention for evaluation. In this way it is concluded that cell permeation and the blood -brain barrier modules merit more evaluation work whereas work on the HERG K þ and CNS activity modules was discontinued.

Lead optimization studies using 7 as the starting point led to a new class of imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases that possessed the 1-benzylpiperazinyl motif at the 7-position, and displayed favorable in vitro properties. Cocrystallization of Aurora-A with 40c (CCT137444) provided a clear understanding into the interactions of this novel class of inhibitors with the Aurora kinases. Subsequent physicochemical property refinement by the incorporation of solubilizing groups led to the identification of 3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole (51, CCT137690) which is a potent inhibitor of Aurora kinases (Aurora-A IC(50) = 0.015 +/- 0.003 muM, Aurora-B IC(50) = 0.025 muM, Aurora-C IC(50) = 0.019 muM). Compound 51 is highly orally bioavailable, and in in vivo efficacy studies it inhibited the growth of SW620 colon carcinoma xenografts following oral administration with no observed toxicities as defined by body weight loss.

Six morpholine-(iso)thiosemicarbazone hybrids HL1–HL6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L1–6)Cl] (1–6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2–5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2–5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.

Using density functional theory (DFT), the hydrogen bonds making up the adenine-thymine (A-T) base pair are found to increase in total energy upon one-electron oxidation or reduction by 10.9 and 13.3 kcal mol À1 , respectively. Due to unsymmetric changes in the H-bond lengths, this strengthening affects an expansion of the base pair length (N1 0 -N9) by $0.27 A ˚. In the oxidized pair, A + -T, deprotonation from N 6 , and with the reduced pair, A À -T, protonation on N3 or N7 lead to base pairs which have similar base pairing energies as their parent A-T, i.e., the stabilization by the change in oxidation state is annihilated by (de)protonation. The calculated proton affinities of A À -T are large enough to explain its protonation by H 2 O, which involves heterolytic bond cleavage of a water molecule. The N1 protonated electron adduct of A is a powerful H-bond donor; it is able to mismatch with cytosine (À28.9 kcal mol À1 ). In DNA this could compete with the '' legitimate '' guanine-cytosine pairing. The pairing abilities of 2-aminopurine, an '' unnatural '' isomer of A, used as a fluorescent probe in DNA assemblies, are calculated to resemble those of A closely.

No abstract

No abstract

The RAPTA pharmacophore was linked to beads to identify its biomolecular targets in cancer cells.

The D3h symmetric tris(dialkylamino)trioxatriangulenium ((R2N)3TOTA+) ions are structurally related to classical stains and fluorophores such as triphenylmethane dyes and rhodamines. New derivatives of (R2N)3TOTA+, in which long flexible alkyl chains surround the planar and rigid aromatic core, have been synthesized and isolated as hexafluorophosphate salts. In contrast to short-chain derivatives of triphenylmethane dyes, the new compounds described here are soluble in hydrocarbon solvents. The photophysical properties of these carbenium salts are investigated. Characteristic alterations of the photophysical properties as a function of solvent polarity, concentration and temperature are observed. A model to rationalize the phenomena is presented comprising three states of aggregation, i.e. freely solvated ions, tight ion-pairs, and dimers of ion-pairs. Reduced symmetry in the tight ion-pairs is held responsible for the observed splitting of the long wavelength absorption band. Exciton coupling in the ion-pair dimers leads to reduced oscillator strength of the S0-S1 transition. The model is supported by semi-empirical calculations of the structures and electronic transitions of the free cation and its ion-pair(s).