Synthesis, biological evaluation and X-ray analysis of bicalutamide sulfoxide analogues for the potential treatment of prostate cancer.

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in anticancer activity across the four PC cell lines with IC50 = 9.09 - 31.11 µM compared to the positive controls: bicalutamide (IC50 = 45.20 -51.61 µM) and enzalutamide (IC50 = 11.47 - 53.04 µM). Sulfoxide derivatives of bicalutamide were prepared efficiently from the corresponding sulfides using only one equivalent of mCPBA, limiting the reaction time to 15-30 min and maintaining the temperature at 0 °C. Interestingly, three pairs of sulfoxide diastereomers were separated and NMR comparison of their diastereotopic methylene (CH2) group is presented. X-ray diffraction crystal structure analysis provided relative configuration assignment at the chiral sulfur and carbon centres. Molecular modelling study of the four diastereoisomers of compound 28 is described.

Local Desymmetrization through Diastereotopic Group Selection: An Enabling Strategy for Natural Product Synthesis.

The application of desymmetrization strategies in chemical synthesis has allowed fundamentally new synthetic sequences that efficiently create dense and polyfunctional stereochemical arrays. Enantiotopic group discrimination has become a well-established method of global desymmetrization, while the conceptually unique strategy of local desymmetrization by diastereotopic group discrimination has its own advantages. This microreview focuses on the application of local desymmetrization in natural product synthesis and places a particular emphasis on the efficiency engendered by diastereotopic group discrimination. Local desymmetrization is subdivided into three distinct manifolds; examples under each paradigm are presented and compared.

19F-NMR Diastereotopic Signals in Two N-CHF2 Derivatives of (4S,7R)-7,8,8-Trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole.

In this paper, we report the anisochrony of the fluorine atoms of a CHF2 group when linked to a pyrazole ring. The pyrazole is part of (4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole also known as (4S,7R)-campho[2,3-c]pyrazole, which has two stereogenic centers. Gauge-Independent Atomic Orbital (GIAO)/Becke, 3-parameter, Lee-Yang-Parr (B3LYP)/6-311++G(d,f) calculated 19F chemical shifts of the minimum energy conformations satisfactorily agree with the experimental data. The energy differences between minima need to consider solvent effects (continuum model) to be satisfactorily reproduced.

Diastereotopic groups in two new single-enanti-omer structures (R2)P(O)[NH-(+)CH(C2H5)(C6H5)] (R = OC6H5 and C6H5).

The crystal structures of two single-enanti-omer compounds, i.e. diphenyl [(R)-(+)-α-ethyl-benzyl-amido]-phosphate, C21H22NO3P or (C6H5O)2P(O)[NH-(R)-(+)CH(C2H5)(C6H5)] (I), and N-[(R)-(+)-α-ethyl-benz-yl]-P,P-di-phenyl-phosphinic amide, C21H22NOP or (C6H5)2P(O)[NH-R-(+)CH(C2H5)(C6H5)] (II), were studied. The different environments at the phospho-rus atoms, (O)2P(O)(N) and (C)2P(O)(N), allow the P=O/P-N bond strengths to be compared, as well as the N-H⋯O=P hydrogen-bond strengths, and P=O/N-H vibrations. The following characteristics related to diastereotopic C6H5O/C6H5 groups in I/II were considered: geometry parameters, contributions to the crystal packing, solution 13C/1H NMR chemical shifts, conformations, and NMR coupling constants. The phospho-rus-carbon coupling constants nJ PC (n = 2 and 3) in I and mJ PC (m = 1, 2, 3 and 4) in II were evaluated. For a comparative study, chiral analogous structures were retrieved from the Cambridge Structural Database (CSD) and their geometries and conformations are discussed.

Structural differences/similarities of diastereotopic groups in three new chiral phosphoramides.

The crystal structures of two single-enantiomer amidophosphoesters with an (O)2P(O)(N) skeleton and one single-enantiomer phosphoric triamide with an (N)2P(O)(N) skeleton were studied. The compounds are diphenyl [(R)-(+)-α-4-dimethylbenzylamido]phosphate, (I), and diphenyl [(S)-(-)-α-4-dimethylbenzylamido]phosphate, (II), both C21H22NO3P, and N-(2,6-difluorobenzoyl)-N',N''-bis[(R)-(+)-α-ethylbenzyl]phosphoric triamide, C25H28F2N3O2P, (III). The asymmetric units contain two amidophosphoester molecules for (I) and (II), and one phosphoric triamide molecule for (III). In the crystal structures of (I) and (II), molecules are assembled in a similar one-dimensional chiral ribbon architecture, but with almost a mirror-image relationship with respect to each other through N-H...O(P) and C-H...O(P) hydrogen bonds along [010]. In the crystal structure of (III), the chiral tape architecture along [100] is mediated by N-H...O(P) and N-H...O(C) hydrogen bonds, and the tapes are connected into slabs by C-H...O interactions (along the ab plane). The differences/similarities of the two diastereotopic phenoxy groups in (I)/(II) and the two chiral amine fragments in (III) were studied on the grounds of geometry, conformation and contribution to the crystal packing, as well as 1H and 13C signals in a solution NMR study.

Two single-enantiomer amidophosphoesters: a database study on the chirality of (O)2P(O)(N)-based structures.

The crystal structures of two single-enantiomer amidophosphoesters with an (O)2P(O)(N) skeleton, i.e. diphenyl [(R)-(+)-α-methylbenzylamido]phosphate, (I), and diphenyl [(S)-(-)-α-methylbenzylamido]phosphate, (II), both C20H20NO3P, are reported. In both structures, chiral one-dimensional hydrogen-bonded architectures, along [010], are mediated by N-H...OP interactions. The statistically identical assemblies include the noncentrosymmetric graph-set motif C(4) and the compounds crystallize in the chiral space group P21. As a result of synergistic co-operation from C-H...O interactions, a two-dimensional superstructure is built including a noncentrosymmetric R44(22) hydrogen-bonded motif. A Cambridge Structural Database survey was performed on (O)2P(O)(N)-based structures in order to review the frequency of space groups observed in this family of compounds; the hydrogen-bond motifs in structures with chiral space groups and the types of groups inducing chirality are discussed. The 2,3JX-P (X = H or C) coupling constants from the NMR spectra of (I) and (II) have been studied. In each compound, the two diastereotopic C6H5O groups are different, which is reflected in the different chemical shifts and some coupling constants.