Novel Alkynylphosphonate Analogue of Calcitriol with Potent Antiproliferative Effects in Cancer Cells and Lack of Calcemic Activity

The Journal of Steroid Biochemistry and Molecular Biology

Obiol

Alonso

et al. 2019

Self Cite

Calcitriol analogs have shown promising potential as compounds to be used in cancer chemotherapy. This report presents the synthesis of a novel vitamin D 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.

“…Instead, calcitriol produced an increase in total and ionized calcium and decreased the body weight, provoking the death of the animals following 72 h, as previously described [9,11].…”

Section: Ml-344 Decreases the Invasive Capacity Of Mammary Cell Linessupporting

confidence: 53%

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

The Journal of Steroid Biochemistry and Molecular Biology

Obiol

Alonso

et al. 2019

Self Cite

“…The health condition of the animals was recorded. Plasma calcium levels were measured by reading the absorbance of metallochromic indicator Arsenazo III AA, as previously described . Interestingly, UVB1 showed no hypercalcemic activity, although a tendency to increase plasma calcium levels within the normal range was observed when comparing with vehicle‐treated animals (Fig.…”

Section: Resultsmentioning

confidence: 96%

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

Salomón

Fermento

et al. 2015

Archiv der Pharmazie

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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.

“…This concentration was also shown to exceed the concentration needed to produce the antitumor effect in vivo. Blood was collected daily prior and following administration of the analogue or vehicle and plasma calcium levels were analyzed as previously described . As evidence of toxicity, hematocrit variation was recorded.…”

Section: Resultsmentioning

confidence: 99%

Novel calcitriol analogue with an oxolane group: In vitro, in vivo, and in silico studies

Obiol

Martínez

et al. 2019

Archiv der Pharmazie

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The active form of vitamin D3, calcitriol, is a potent antiproliferative compound. However, when effective antitumor doses of calcitriol are used, hypercalcemic effects are observed, thus blocking its therapeutic application. To overcome this problem, structural analogues have been designed with the aim of retaining or even increasing the antitumor effects while decreasing its calcemic activity. This report aims at gaining insights into the structure–activity relationships of the novel oxolane‐containing analogue, AM‐27, recently synthesized. We herein demonstrate that this compound has antiproliferative and antimigratory effects in squamous cell carcinoma, glioblastoma, and breast cancer cell lines. Analyses of the mechanisms underlying the AM‐27 effects on cell viability revealed induction of apoptosis by the analogue. Importantly, nonmalignant cell lines were little or not affected by the compound. In addition, the analogue did not produce hypercalcemia in mice. Also, in silico studies involving docking and molecular dynamics techniques showed that AM‐27 is able to bind to the human vitamin D receptor with a higher affinity than the natural ligand calcitriol, a feature that is mostly derived from an electrostatic interaction pattern. Altogether, the proapoptotic effect observed in cancer cells, the lack of calcemic activity in mice, and the differential effects in normal cells suggest the potential of AM‐27 as a therapeutic compound for cancer treatment.