Stella H. Maganhi

Preaustinoid A: a meroterpene produced by Penicillium sp.

The title meroterpene preaustinoid A (systematic name: methyl 15-hydroxy-2,6,6,10,13,15-hexamethyl-17-methylene-7,14,16-trioxotetracyclo[11.3.1.02,11.05,10]heptadecane-1-carboxylate), C26H36O6, features a fused four-ring arrangement. Three rings are in different distorted chair conformations and the other is in a distorted boat conformation. The absolute configuration was established based on [αD] = −4.97° (c = 1.10 g l−1, CH2Cl2). In the crystal, the molecules are connected into supramolecular chains via O—H⋯O hydrogen bonds.

Palbociclib can overcome mutations in cyclin dependent kinase 6 that break hydrogen bonds between the drug and the protein

Inhibition of cyclin dependent kinases (CDKs) 4 and 6 prevent cells from entering the synthesis phase of the cell cycle. CDK4 and 6 are therefore important drug targets in various cancers. The selective CDK4/6 inhibitor palbociclib is approved for the treatment of breast cancer and has shown activity in a cellular model of mixed lineage leukaemia (MLL)‐rearranged acute myeloid leukaemia (AML). We studied the interactions of palbociclib and CDK6 using molecular dynamics simulations. Analysis of the simulations suggested several interactions that stabilized the drug in its binding site and that were not observed in the crystal structure of the protein‐drug complex. These included a hydrogen bond to His 100 that was hitherto not reported and several hydrophobic contacts. Evolutionary‐based bioinformatic analysis was used to suggest two mutants, D163G and H100L that would potentially yield drug resistance, as they lead to loss of important protein–drug interactions without hindering the viability of the protein. One of the mutants involved a change in the glycine of the well‐conserved DFG motif of the kinase. Interestingly, CDK6‐dependent human AML cells stably expressing either mutant retained sensitivity to palbociclib, indicating that the protein‐drug interactions are not affected by these. Furthermore, the cells were proliferative in the absence of palbociclib, indicating that the Asp to Gly mutation in the DFG motif did not interfere with the catalytic activity of the protein.

Crystallographic, DFT and docking (cathepsin B) studies on an organotellurium(IV) compound

Abstract Some biologically active organotellurium compounds exhibit inhibitory potency against cathepsin B. In this study, an alkyl derivative, viz. [CH3(CH2)2C(I)=C(H)](nBu)TeI2, 1, has been structurally characterised by X-ray crystallography and shown to be coordinated within a C2I2 donor set. When the stereochemically active lone pair of electrons is taken into account, a distorted trigonal bipyramidal geometry results with the iodide atoms in axial positions. Both intra- and inter-molecular Te···I interactions are also noted. If all interactions are considered, the coordination geometry is based on a Ψ-pentagonal bipyramidal geometry. An unusual feature of the structure is the curving of the functionalised C5 chain. This feature has been explored by DFT methods and shown to arise as a result of close C–H···I interactions. A docking study (cathepsin B) was performed to understand the inhibition mechanism and to compare the new results with previous observations. Notably, 1 has the same pose exhibited by analogous biologically active compounds with aryl groups. Thus, the present study suggests that (alkyl)2TeX2 compounds should also be evaluated for biological activity.

Triterpenoids as Novel Natural Inhibitors of Human Cathepsin L

Cathepsins L (catL) and B play an important role in tumor progression and have been considered promising therapeutic targets in the development of novel anticancer agents. Using a bioactivity‐guided fractionation, a series of triterpenoids was identified as a new class of competitive inhibitors towards cathepsin L with affinity values in micromolar range. Among the 14 compounds evaluated, the most promising were 3‐epiursolic acid (3), 3‐(hydroxyimino)oleanolic acid (9), and 3‐(hydroxyimino)masticadienoic acid (13) with IC50 values of 6.5, 2.4, and 2.6 μM on catL, respectively. Most of the evaluated triterpenoids do not inhibit cathepsin B. Thus, the evaluated compounds exhibit a great potential to help in the design of new inhibitors with enhanced potency and affinity towards catL. Docking studies were performed in order to gain insight on the binding mode and SAR of these compounds.

N-[(1,3-Benzodioxol-5-yl)meth­yl]-4-methyl­benzamide: an analogue of capsaicin

In the title compound, C16H15NO3, the five-membered 1,3-dioxole ring is in an envelope conformation with the methylene C atom as the flap atom [lying 0.202 (3) Å out of the plane formed by the other four atoms]. The benzene ring makes a dihedral angle of 84.65 (4)° with the best least-squares plane through the 1,3-benzodioxole fused-ring system, which substitutes the 2-methoxyphenol moiety in capsaicin. In the crystal, molecules are connected into a zigzag supramolecular chain along the c-axis direction by N—H⋯O hydrogen bonds. These chains are connected into a layer in the ac plane by C—H⋯π interactions.

Crystal structure of 3-[2-(4-methyl-phen-yl)ethyn-yl]-2H-chromen-2-one.

The coumarin ring system in the title asymmetric alkyne, C18H12O2, is approximately planar (r.m.s. deviation of the 11 non-H atoms = 0.048 Å), and is inclined with respect to the methylbenzene ring, forming a dihedral angle of 33.68 (4)°. In the crystal, supramolecular zigzag chains along the c-axis direction are formed via weak C—H⋯O hydrogen bonds, and these are connected into double layers via weak C—H⋯π interactions; these stack along the a axis.

Crystal structure of (3E)-3-(2,4-di­nitro­phen­oxy­meth­yl)-4-phenyl­but-3-en-2-one

In the title compound, C17H14N2O6, the conformation about the C=C double bond [1.345 (2) Å] is E, with the ketone moiety almost coplanar [C—C—C—C torsion angle = 9.5 (2)°] along with the phenyl ring [C—C—C—C = 5.9 (2)°]. The aromatic rings are almost perpendicular to each other [dihedral angle = 86.66 (7)°]. The 4-nitro moiety is approximately coplanar with the benzene ring to which it is attached [O—N—C—C = 4.2 (2)°], whereas the one in the ortho position is twisted [O—N—C—C = 138.28 (13)°]. The molecules associate via C—H⋯O interactions, involving both O atoms from the 2-nitro group, to form a helical supramolecular chain along [010]. Nitro–nitro N⋯O interactions [2.8461 (19) Å] connect the chains into layers that stack along [001].

N-[(1,3-Benzodioxol-5-yl)meth­yl]benzene­sulfonamide: an analogue of capsaicin

The title compound, C14H13NO4S, an analogue of capsaicin, differs from the latter by having a 1,3-benzodioxole ring rather than a 2-methoxyphenol moiety, and having a benzenesulfonamide group instead of an aliphatic amide chain. The five-membered ring is in an envelope conformation with the methylene C atom lying 0.221 (6) Å out of the plane formed by the other four atoms. The dihedral angle between the phenyl ring and the mean plane of the 1,3-benzodioxole fused-ring system is 84.65 (4)°. In the crystal, molecules aggregate into supramolecular layers in the ac plane through C—H⋯O, N—H⋯O and C—H⋯π interactions.

Molecular Structures of Isomeric Ortho, Meta, and Para Bromo-Substituted α-Methylsulfonyl-α-diethoxyphosphoryl Acetophenones by X-ray and DFT Molecular Orbital Calculations

The X-ray single crystal analysis of isomeric ortho, meta, and para bromo-substituted α-methylsulfonyl-α-diethoxyphosphoryl acetophenones showed that this class of compound adopts synclinal (gauche) conformations for both [-P(O)(OEt)2] and [-S(O)2Me] groups, with respect to the carbonyl functional group. The phosphonate, sulfonyl, and carbonyl functional groups are joined through an intramolecular network of attractive interactions, as detected by molecular orbital calculations at the M06-2X/6-31G(d,p) level. These interactions are responsible for the more stable conformations in the gas phase, which also persist in the solid-state structures. The main structural distinction in the title compounds relates to the torsion angle of the aryl group (with respect to the carbonyl group), which gives rise to different interactions in the crystal packing, due to the different positions of the Br atom.

Crystal structure of 3-[2-(thio-phen-3-yl)ethyn-yl]-2H-chromen-2-one.

In the title compound, C15H8O2S, the coumarin moiety is approximately planar (r.m.s. deviation of the 11 non-H atoms = 0.025 Å) and is slightly inclined with respect to the plane of the thiophen-3-yl ring, forming a dihedral angle of 11.75 (8)°. In the crystal, the three-dimensional architecture features a combination of coumarin–thiophene C—H⋯π and π–π [inter-centroid distance = 3.6612 (12) Å] interactions.