Synthesis and crystal structure of a new anticancer candidate: RPF151

This work reports on the synthesis, crystal structural determination, conformational analysis and antiproliferative activity of an alkylsulfonamide analogue of capsaicin – RPF151 (N-(benzo[d][1,3]dioxol-5-ylmethyl)butane-1-sulfonamide). Capsaicin is the primary pungent and irritating natural product present in a variety of red chilli peppers of the genus Capsicum, and was reported to selectively inhibit the growth and to induce apoptosis in a wide variety of tumour cell lines.1-3 RPF151 was obtained by a simple reaction of 1-butanesulfonyl chloride with piperonylamine, in an anhydrous DCM (dichloromethane) and TEA (tetraethylammonium) mixture (Yield 70%). The crystal structure determination was carried out by means of an ab initio simulated annealing approach using X-ray powder diffraction data. RPF151 crystallized under a monoclinic system (P21/a) with final unit cell parameters refined using the Rietveld method: a = 29.0171(13) Å, b = 10.4745(3) Å, c = 9.1117(3) Å, β = 104.268(4)⁰, V = 2683.98(17) Å3, Z = 8, Z' = 2. The statistical parameter as well as R-factors were: χ2 = 1.11, Rwp = 0046, Rexp = 0.042 and RBragg = 0.010. The molecules are held together along the c-axis by hydrogen bonds involving the atoms N(37)–H(42)···O(4). Calculated elemental analysis for C12H17NO4S (271.09 g mol-1) shows C = 53.12, H = 6.32 and N = 5.16 while experimental values are C = 53.13, H = 6.39 and N = 5.14. The effects of RPF151 10 μM on human umbilical vein endothelial cells (HUVEC) proliferation was tested by flow cytometry. It was verified that RPF151 induced changes on cell morphology, a fact corroborated by HUVEC cell size and complexity. Furthermore, it caused a significant reduction on cell proliferation and evidenced no cytotoxic effects. Therefore, RPF151 could be developed as a candidate to an anti-angiogenic drug for the fighting against cancer. Acknowledgments: We are grateful to FAPESP (proc. nr.: 2013/18160-4, 2012/23233-8 and 2008/10537-3), CNPq (proc. nr. 305186/2012-4 and 477296/2011-4) and Provost's Office for Research of the University of São Paulo for financial support.

Structural Characterization of Albendazole with the Use of X-Ray Diffraction

Drugs may present polycrystalline polymorphism (property of a substance to crystallize in more than one form or crystal structure). These variations can cause changes in physical-chemical properties and differences between the polymorphs as shape, solubility, density, melting range, among other consequences, leading to formulations that are not effective, although the chemical formula is the same [1]. Drugs such as albendazole (C12H15N3O2S, which is one of the most effective anthelmintics, [2] showing activity against nematodes, trematodes and cestodes, reasons that added to its safety and low cost have made it a drug widely used in human medicine and veterinary), has more than two different crystal structures, and only two of them are known. The X-ray powder diffraction is a powerful technique used in the structural characterization of drugs, and coupled with the Rietveld method [4], the quantification of the active phases, through the knowledge of their crystal structures, becomes possible. In this paper we discuss results on the differences between the polymorphs of albendazole, with data obtained by means of X-ray diffraction, thermal analysis (differential scanning calorimetry and thermogravimetric analysis), Fourier transform infrared spectroscopy and scanning electron microscopy.

Structure Determination of LASSBio-1289: A New Antihypertensive Lead-Compound

Hypertension is considered a multi-factorial disease being an important worldwide public-health challenge due to its high frequency and concomitant risks of cardiovascular and other diseases. It has been identified as the leading risk factor for mortality, and is ranked as the third cause of disability-adjusted life-years[1]. The LASSBio-1289 compound was designed from the lead compound LASSBio-294 through the use of medicinal chemistry strategy of bioisosteric replacement of aromatic rings[2]. Many factors are involved in the task of describing the relationship between chemical structure and pharmacological activity of a prototype of a new drug. Among these factors the study of atomic-level structure can be included. The aim of this work is to carry out the structural characterization of LASSBio-1289, in solid-state. Since many NAH derivatives, as LASSBio-1289, do not form single crystals for proper structure determination, this task was overcome by using X-ray powder diffraction data and an ab initio simulated annealing procedure. This study can contribute to better understand the full pharmacodynamic profiles and physicochemical properties of this class of compounds. The LASSBio-1289 compound was synthesized following the procedure described in literature[3]. The sample was sofly hand-grinded in an agate mortar in order to get a fine powder suitable for X-ray powder diffraction analysis. The final refined values for the unit-cell parameters after the Rietveld fit were: a = 14.5119(3) Å, b = 12.1375(2) Å, c = 7.5498(1) Å, β = 91.113(1) Å, Z = 4, Z' = 1 and ρcalc = 1.44039(5) g.m-3. The goodness-of-fit indicator and R-factors were: χ2 = 1.290, RBragg = 1.749%, Rwp = 4.903%, Rexp = 3.802% and Rp = 3.661%. The crystal structure of LASSBio-1289 compound consists of four formula units per unit cell (Z = 4), accommodating one molecule in the asymmetric unit (Z' = 1). The sample was indexed as monoclinic space group (P21/c).