Biological evaluations of novel 2,3,3-Trisphosphonate in osteoclastic and osteoblastic activities

Abstract

Bisphosphonates (BPs) are the first line treatment for many bone diseases including hypercalcimia associated with bone malignancies. In this paper, we introduce a new analogue of bisphosphonate called the 2,3,3-Trisphosphonate (2,3,3-TriPP) that was synthesised in a two steps reaction. In vitro investigations using a medically known bisphosphonate (Etidronate) and the 2,3,3-TrisPP were performed with an aim to evaluate biological effect of this novel compound in major bone cells. 2,3,3-TrisPP showed to have potential to supress the bone resorption process, as our data found that this novel compound exhibited cytotoxic effect in osteoclastic cells at a low concentration of 0.172 mg/mL (LC 50 ). A molecular docking computational simulation calculated a high level of binding affinity between the human farnesyl pyrophosphate synthase (hFPPS) and 2,3,3-TrisPP. This calculation suggested 2,3,3TrisPP may have undergone the mevalonate pathway to prevent the prenylation step during biosynthesis and subsequently resulted in the deactivation of osteoclastic cells. Finally, high levels of osteoblast mineralisation potentials were recorded upon treatments with 2,3,3-TrisPP (0.01-0.1 mg/ml), which implied 2,3,3-TrsiPP may also facilitate bone regeneration.

Bisphosphonate-Based Molecules as Potential New Antiparasitic Drugs

“…Similar to pyrophosphate, bisphosphonates exhibit a high affinity for bone hydroxyapatite and effectively prevent calcification [44]. The Food and Drug Administration (FDA) currently approves some of these compounds for the treatment of bone resorption, Paget's disease, osteoporosis, multiple myeloma, hypercalcemia associated with bone metastasis, and fibrous dysplasia [14,15,45]. On the other hand, in addition to their capacity as inhibitors of bone resorption, bisphosphonates are antimicrobial agents [46], anticancer agents [47], selective inhibitors of acid sphingomyelinase, and stimulators of γδ-T lymphocytes [48].…”

“…Disorders in this metabolic pathway can cause toxicity, alteration of cellular structure and function, as well as loss of homeostasis [84]. Experimental evidence has shown that second-and third-generation nitrogenous bisphosphonates are generally more potent than conventional bisphosphonates in inhibiting bone resorption [14,82]. However, the main disadvantage of administering these compounds is related to toxicity, as it can induce the development of severe osteonecrosis and gastric inflammation in humans [70,86].…”

“…Conventional bisphosphonates participate in metabolic reactions, mainly in ATP biosynthesis. On the other hand, nitrogenous bisphosphonates can act on the mevalonate pathway through the inhibition of the FPPS enzyme [14]. The FPPS enzyme catalyzes two-step reactions.…”

“…The FPPS enzyme catalyzes two-step reactions. In the first step, isopentenyl pyrophosphate (IPP) and its dimethylalyl pyrophosphate isomer (DMAPP) undergo condensation to form geranyl pyrophosphate (GPP) and farnesyl pyrophosphate (FPP), important isoprenoid intermediates [8,14]. Isopropenoids are essential molecules of the cellular machinery of eukaryotic and prokaryotic organisms, as an example, the trypanosomatids parasites and bacteria, respectively.…”

“…In this scenario, compounds based on bisphosphonates have been gaining prominence owing to their reported antiparasitic activity [7][8][9][10][11][12][13]. Moreover, some of these compounds are already approved for use in humans for the treatment of some bone diseases [14,15]. Bisphosphonates are known to act on the classical mevalonate (MVA) pathway, which is responsible for the synthesis of essential isoprenoids in eukaryotes, archaea, and some bacterial species [16,17].…”