Ram Thaimattam

Protein Kinase Inhibitors: Structural Insights Into Selectivity

Protein kinases are involved in many diseases like cancer, inflammation, cardiovascular disease, and diabetes. They have become attractive target classes for drug development, making kinase inhibitors as important class of therapeutics. The success of small-molecule ATP-competitive kinase inhibitors such as Gleevec, Iressa, and Tarceva has attracted much attention in the recent past. Kinases make use of ATP for phosphorylation of a specific residue(s) on their protein substrates. More than 400 X-ray structures of about 70 different kinases are publicly available. These structures provide insights into selectivity and mechanisms of inhibition. However, prediction of binding specificity of kinase inhibitors based on structural information alone appears to be insufficient. Here, we will review these observations to gain insights into the rules that govern protein kinase inhibitor selectivity.

Supramolecular synthons mediated by weak hydrogen bonding: forming linear molecular arrays via CC–H···NC and CC–H···O2N recognition

In crystalline 4-cyano-4′-ethynylbiphenyl and 4-ethynyl-4′-nitrobiphenyl, molecules are connected with the hitherto unreported Câ–·C–H···Nâ–·C and Câ–·C–H···O2N supramolecular synthons to form linear arrays.

Design of an SHG-active crystal, 4-iodo-4′-nitrobiphenyl: the role of supramolecular synthons

The crystal structure of 4-iodo-4′-nitrobiphenyl has been determined with packing calculations and the presence of polar and parallel iodo···nitro supramolecular synthons leads to non-centrosymmetry and measurable SHG activity

Molecular networks in the crystal structures of tetrakis(4-iodophenyl)methane and (4-iodophenyl)triphenylmethane

The crystal structure of tetrakis(4-iodophenyl)methane is analysed in terms of molecular networks wherein the tetraphenylmethane moieties and I4 synthons are considered as molecular and supramolecular nodes. This I4 cluster plays the same role in generating molecular networks as does the Br4 cluster in the isomorphous tetrakis(4-bromophenyl)methane derivative. (4-Iodophenyl)triphenylmethane crystallises in a lower symmetry space group but features an unusual I···Ph interaction. In this series of halo-substituted tetraphenylmethanes the molecules exhibit similar columnar packing in the solid state, accounting for their crystallisation in non-centrosymmetric space groups.

Polytypism in desvenlafaxine succinate monohydrate

Two polytypes of desvenlafaxine succinate monohydrate, an antidepressant drug, contain essentially identical 2-D layers, but with different stacking arrangements, which is quite rare in organic compounds.

Extending the supramolecular synthon concept in flexible polyaminocarboxylate based coordination polymers

Six coordination polymers (CPs) of 1,3,5-triazine-2,4,6-triamine hexaacetic acid (TTHA) with various metals (M = Na, solid 1; M = Mg, solid 2; M = Cu, solids 3a and 3b; and M = Zn, solids 4a and 4b) are reported and analyzed in terms of supramolecular synthons. [Na4(H3TTHA)Cl(H2O)], 1 and [Mg2(H2TTHA)(H2O)], 2 are 3D CPs involving trinuclear Na(I) clusters and two distinct (24- and 16-membered) acid–Mg(II) dimer synthons, respectively. With Cu, TTHA forms 1D and 2D CPs, [Cu2(H2TTHA)(H2O)6], 3a and [Cu2(H2TTHA)(H2O)4]·4H2O, 3b, respectively with distinct compositions. The 24-membered acid–Cu(II) dimer synthon is responsible for 1D aggregation in 3a, while alternating 24- and 4-membered acid–Cu(II) dimer synthons lead to the formation of a 2D metal–organic network in 3b. Two compositional variants are also observed with Zn: an acid–Zn(II) dimer synthon leads to the formation of a 3D CP in [Zn5Na2(TTHA)2(H2O)8], 4a and a 1D CP in [Zn2(H2TTHA)(H2O)7]·2H2O, 4b. In Cu and Zn based CPs, the crystal form is determined by the protonation states of TTHA and the method of preparation. The application of the synthon concept made structural analyses of CPs simple, which revealed structural relationships not only among them, but with the reported TTHA polymorphs.

Structural landscape of multicomponent solids based on sulfa drugs

Our attempts to cocrystallize three sulfa drugs (SDs), viz., sulfamerazine (smr), sulfamethazine (smz) and sulfamethoxazole (smx) with four coformers, viz., niflumic acid and flufenamic acid, 4-aminopyridine and piperazine led to eight new solids. Although the molecular structures of smr, smx and smz are comparable, their propensities to form multiple solid forms with the four selected coformers were found to be different. smr and smx reacted with 4-aminopyridine and piperazine yielding four salts while its reaction with niflumic and flufenamic acids resulted in the precipitation of only the reactants. In contrast, smz formed cocrystals with niflumic and flufenamic acids and salts with 4-aminopyridine and piperazine. To understand this discrepancy, we investigated the structural chemistry of these solids by analysing the interactions of key synthons present in the single component SDs as well as those reported in the literature. The study reveals that recognition of the nature of key synthons occurring in single component SDs and the ability to break and form new synthons with coformers can be a viable strategy to design multicomponent solids based on sulfa drugs.

Multicomponent solids of uracil derivatives – orotic and isoorotic acids

Cocrystallization of two multifunctional structural isomers viz. orotic and isoorotic acids was explored with a series of amine and pyridine-based coformers. The system has been chosen in such a way so that robustness of the acid⋯pyridine synthon was tested against competing amine⋯pyridine and carbonyl⋯pyridine synthons. Here, we report the structural characterization and solubility measurements of ten solids which include three cocrystals, one salt cocrystal, four salts and two salt hydrates. All multicomponent solids showed significant improvement in solubility in comparison to the acids and also showed a strong correlation between the percentage of the O⋯H interaction and solubility. The ΔpKa rule is validated in the structural landscape by considering all components of the matrix together.

Structural landscape of multicomponent solids of 5-aminosalicylic acid

Crystallization of ten new multicomponent solids of 5-aminosalicylic acid with various inorganic and organic coformers has been achieved by mechanochemical and solvent evaporation techniques. The structural description of all the solids has been described in terms of robust ring motifs and supramolecular acid⋯pyridine synthons. The R44(12) motif is the key structural unit appearing in almost all the multicomponent solids formed in the presence of inorganic and organic acids and this is further verified with other related structures reported in the CSD database. The choice of a structural model between a cocrystal and a salt for the different solids was further ascertained by ATR study.

Engineering multicomponent solids based on fenamates

Nonsteroidal anti-inflammatory drugs (nsaids) are among the most commonly used pharmaceutical solids and primarily used as anti-inflammatory, analgesic, and antipyretic agents.1 In this study we focused on two nsaids molecules Niflumic acid (Nif) and Mefenamic acid (Mef) which are BCS (Biopharmaceutical classification system) class II drug with poor solubility and high permeability.2 Both these molecules have important pharmacological activity. The first drug Nif used in rheumatoid arthritis and arthrosis the second drug Mef prescribed in conditions of dental pain, premenstrual syndrome, headache and postoperative surgeries. Recently Mef is also found to have therapeutic effect in Alzheimer’s diseases and anti-cancer activity (colon and liver cancer).3 We extended our approach to exploit acid···pyridine synthon to obtain new multicomponent solids based on Nif and Mef. In this poster, we discuss the design strategy, comparative structural features of twelve new solids based on Nif and Mef.