Marcos L. Rivadulla

Vitamin D Analogue: Potent Antiproliferative Effects on Cancer Cell Lines and Lack of Hypercalcemic Activity

The active form of vitamin D3, 1α,25(OH)2D3, plays a major role in maintaining calcium/phosphate homeostasis. In addition, it is a potent antiproliferative and pro‐differentiating agent. Unfortunately, it usually causes hypercalcemia in vivo when effective antitumour doses are used. It has therefore been found necessary to synthesise new analogues that retain or even increase the antitumour effects but preclude hypercalcemia. This report presents the synthesis of a novel Gemini vitamin D analogue (UVB1) and its biological evaluation. We demonstrate that this compound has potent antitumoural effects over a wide panel of tumour cell lines while showing lack of hypercalcemic activity and toxicity effects in in vivo assays.

The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression.

Vitamin D has been shown to display a wide variety of antitumour effects, but their therapeutic use is limited by its severe side effects. We have designed and synthesized a Gemini vitamin D analogue of calcitriol (UVB1) which has shown to display antineoplastic effects on different cancer cell lines without causing hypercalcemia. The aim of this work has been to investigate, by employing in silico, in vitro, and in vivo assays, whether UVB1 inhibits human colorectal carcinoma progression. We demonstrated that UVB1 induces apoptotic cell death and retards cellular migration and invasion of HCT116 colorectal carcinoma cells. Moreover, the analogue reduced the tumour volume in vivo, and modulated the expression of Bax, E-cadherin and nuclear β-catenin in tumour animal tissues without producing toxic effects. In silico analysis showed that UVB1 exhibits greater affinity for the ligand binding domain of vitamin D receptor than calcitriol, and that several characteristics in the three-dimensional conformation of VDR may influence the biological effects. These results demonstrate that the Gemini vitamin D analogue affects the growth of the colorectal cancer and suggest that UVB1 is a potential chemotherapeutic agent for treatment of this disease.

Gemini Analogs of Vitamin D

The Gemini analogs are the last significant contribution to the family of vitamin D derivatives in medicine, for the treatment of cancer. The first Gemini analog was characterized by two symmetric side chains at C-20. Following numerous modifications, the most active analog bears a C-23-triple bond, C-26, 27- hexafluoro substituents on one side chain and a terminal trideuteromethylhydroxy group on the other side chain. This progression was possible due to improvements in the synthetic methods for the preparation of these derivatives, which allowed for increasing molecular complexity and complete diastereoselective control at C-20 and the substituted sidechains.

N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine (F2MPA): A Potential Cognitive Enhancer with MAO Inhibitor Properties

A considerable body of human and animal experimental evidence links monoaminergic systems and cognition. Monoamine oxidase inhibitors (MAOIs), being able to enhance monoaminergic transmission and having neuroprotective properties, might represent a promising therapeutic strategy in cognitive impairment in Alzheimers disease (AD) and other dementias.

(7aR)-1-[(2R,5S,E)-6-Hy­droxy-5,6-dimethyl­hept-3-en-2-yl]-7a-methyl­hexa­hydro-1H-inden-4(2H)-one

The chiral title compound, C19H32O2, contains a [4.3.0]-bicyclic moiety in which the shared C—C bond presents a trans configuration and a side chain in which the C=C double bond shows an E conformation. The conformations of five- and six-membered rings are envelope (with the bridgehead atom bearing the methyl substituent as the flap) and chair, respectively, with a dihedral angle of 4.08 (17)° between the idealized planes of the rings. In the crystal, the molecules are self-assembled via classical O—H⋯O hydrogen bonds, forming chains along [112]; these chains are linked by weak non-classical C—H⋯O hydrogen bonds, giving a two-dimensional supramolecular structure parallel to (010). The absolute configuration was established according to the configuration of the starting material.

Synthesis of a novel analog of calcitriol and its biological evaluation as antitumor agent

Calcitriol analogs have shown promising potential as compounds to be used in cancer chemotherapy. This report presents the synthesis of a novel vitamin D3 derivative with an amide and a carboxyl group in its side chain, called ML-344. In addition, we report its in vitro antitumor activity and its in vivo calcemic effects. We demonstrate that the analog decreases cell viability and retards cell migration of different breast, glioblastoma and head and neck cancer cell lines. Additionally, unlike calcitriol, ML-344 does not display citotoxicity to the murine non-malignant mammary cells and human astrocytes. In concordance with the antimigratory effects found in breast cancer cells, ML-344 decreased the invasive capacity and induced a rearrangement of the actin cytoskeleton in the LM3 breast cancer cell line. In relation to the in vivo studies, the analog did not cause hypercalcemic effects in CF1 mice administered daily at 5 μg/Kg of body weight during a period of 264 h. Finally, computational studies were performed to evaluate the potential binding of the analog to the vitamin D receptor and the in silico assays showed that ML-344 is able to bind to VDR with interesting particularities and greater affinity than calcitriol. Altogether, these results suggest that ML-344 has a promising potential as an antitumor agent with a differential effect between tumor and non-malignant cells.

[(2S,3aR,6aR)-5-Oxohexa-hydro-furo[3,2-b]furan-2-yl]methyl acetate.

The title compound, C9H12O5, is a bicyclic lactone, presenting a 2,6-dioxabicyclo[3.3.0]octan-3-one skeleton, which was obtained through an intramolecular lactonization. The bicyclic lactone presents a cis ring-junction and a 1,5-trans-substituted tetrahydrofuran. Both five-membered rings are in twisted envelope conformations with one of the fused C atoms as the flap. The dihedral angle between the mean planes of the bicyclic lactone residue, defined by the dihydrofuran-2(3H)-one and the tetrahydrofuran rings, is 69.5 (2)°. The atoms of the ester chain are coplanar [maximum deviation = 0.013 (2) Å]. The absolute structure was not determined.

(1S,2S,5S)-2-Methyl-3-oxo-5-(prop-1-en-2-yl)cyclo­hexane-1-carbo­nitrile

The molecule of the title compound, C11H15NO, contains a cyclohexanone ring, three defined stereocenters and an exocyclic double bond. The crystal structure is the result of a study on the Michael addition reaction of (S)-carvone with sodium cyanide using ionic liquids as the reaction medium and so the absolute configuration is known from the chemistry. The six-membered ring is in a chair conformation.

(3aRS,7aSR)-7a-Meth­oxy-2-oxo-2,3,3a,4,5,6,7,7a-octa­hydro-1-benzofuran-4,4-dicarbonitrile

The racemic title compound, C11H12N2O3, contains a [4.3.0]bicyclic unit in which the shared C—C bond adopts a cis configuration. The five- and six-membered rings are in twisted envelope (with the bridgehead C atom bearing the methoxy substituent as the flap) and distorted chair conformations, respectively. In the crystal, the molecules are linked via weak C—H⋯O iteractions, forming ladder-like chains along [010].