Comparative analysis of risedronate and its regioisomers synthesized via microwave-assisted method: bone affinity, cytotoxicity, permeability, and therapeutic potential.

IF 3.8 3区医学 Q2 PHARMACOLOGY & PHARMACY Pharmacological Reports Pub Date : 2025-04-01 Epub Date: 2025-02-10 DOI:10.1007/s43440-025-00703-y

Monika Zielińska, Amanda Pacholak, Bartosz Orwat, Mariusz Sandomierski, Ireneusz Kownacki, Ewa Kaczorek, Adam Voelkel

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Abstract

Background: Bisphosphonates (BPs) are widely used for treating bone diseases such as osteoporosis due to their strong affinity for hydroxyapatite (HA) in bones. Minor structural variations among BPs can significantly affect their therapeutic potential. This study aimed to synthesize risedronate (RSD) and its two regioisomers (2-RSD, 4-RSD) and investigate the impact of these variations on bone affinity, permeability, and cytotoxicity.

Methods: RSD and its regioisomers were synthesized using a microwave-assisted method. Bone affinity was assessed through sorption studies on HA and two polymer-ceramic materials mimicking bone properties. Compound permeability was predicted using the Parallel Artificial Membrane Permeability Assay (PAMPA). Cytotoxicity was evaluated by analyzing the response of bacterial cells to BPs using metabolic activity assays.

Results: 2-RSD demonstrated a higher bone affinity and similar permeability than commercially available RSD. 2-RSD also showed reduced cytotoxicity in bacterial cell assays, indicating enhanced biocompatibility. These findings suggest that minor structural changes can lead to significant differences in therapeutic efficacy.

Conclusions: The study highlights the potential of the 2-RSD as a more effective treatment for bone diseases. Structural variations in BPs can greatly influence their biological properties, paving the way for the development of improved therapeutic agents.

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微波辅助法合成利塞膦酸钠及其区域异构体的比较分析：骨亲和力、细胞毒性、渗透性和治疗潜力。

背景：双膦酸盐（bp）由于对骨中的羟基磷灰石（HA）具有很强的亲和力，被广泛用于治疗骨质疏松症等骨病。bp之间微小的结构变化会显著影响其治疗潜力。本研究旨在合成利塞膦酸酯（RSD）及其两个区域异构体（2-RSD、4-RSD），并研究这些变异对骨亲和力、通透性和细胞毒性的影响。方法：采用微波辅助法合成RSD及其区域异构体。通过HA和两种模拟骨特性的聚合物陶瓷材料的吸附研究来评估骨亲和力。采用平行人工膜透性测定法（PAMPA）预测复合透性。通过代谢活性测定分析细菌细胞对bp的反应来评估细胞毒性。结果：与市售RSD相比，2-RSD具有更高的骨亲和性和相似的渗透性。2-RSD在细菌细胞试验中也显示出降低的细胞毒性，表明生物相容性增强。这些发现表明，微小的结构变化可能导致治疗效果的显著差异。结论：该研究强调了2-RSD作为一种更有效的骨疾病治疗方法的潜力。bp的结构变化可以极大地影响其生物学特性，为开发改进的治疗剂铺平了道路。

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来源期刊

Pharmacological Reports 医学-药学

CiteScore

8.40

自引率

0.00%

发文量

审稿时长

6 months

期刊介绍： Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures. Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology. Studies of plant extracts are not suitable for Pharmacological Reports.