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基于β-十二硼酸盐阴离子与脂肪族二氨基酸共轭物的新型有前景的硼中子俘获治疗剂的合成

Synthesis of New Promising BNCT Agents Based on Conjugates of -Dodecaborate Anion and Aliphatic Diamino Acids.

作者信息

Ryabchikova Margarita N, Nelyubin Alexey V, Klyukin Ilya N, Selivanov Nikita A, Bykov Alexander Yu, Kubasov Alexey S, Skribitsky Vsevolod A, Finogenova Yulia A, Shpakova Kristina E, Kasianov Anton A, Lipengolts Alexey A, Zhdanov Andrey P, Grigoreva Elena Yu, Zhizhin Konstantin Yu, Kuznetsov Nikolay T

机构信息

Faculty of Chemistry, Higher School of Economics, Myasnitskaya St. 20, 101000 Moscow, Russia.

Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Leninskii Pr. 31, 119991 Moscow, Russia.

出版信息

Int J Mol Sci. 2024 Dec 25;26(1):68. doi: 10.3390/ijms26010068.

DOI:10.3390/ijms26010068
PMID:39795927
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11719580/
Abstract

In this work, a series of boronated amidines based on the -dodecaborate anion and amino acids containing an amino group in the side chain of the general formula [BHNHC(NH(CH)CH(NH)COOH)CH], where n = 2, 3, 4, were synthesized. These derivatives contain conserved α-amino and α-carboxyl groups recognized by the binding centers of the large neutral amino acid transporter (LAT) system, which serves as a target for the clinically applied BNCT agent para-boronophenylalanine (BPA). The paper describes several approaches to synthesizing the target compounds, their acute toxicity studies, and tumor uptake studies in vivo in two tumor models. The promising compound [BHNHC(NH(CH)CH(NH)COOH)CH]*3HO demonstrates low toxicity (LD in a range from 150 to 300 mg/kg) and excellent solubility and also shows selective uptake in experimental melanoma in laboratory mice (T/N ratio remained >3 up to 60 min post-injection, with a maximum T/N of 6.2 ± 2.8 at 45 min).

摘要

在本研究中，合成了一系列基于 -十二硼酸盐阴离子和侧链含有氨基的氨基酸的硼化脒，其通式为[BHNHC(NH(CH)CH(NH)COOH)CH]，其中n = 2、3、4。这些衍生物含有被大中性氨基酸转运体（LAT）系统的结合中心识别的保守α-氨基和α-羧基基团，该系统是临床应用的硼中子俘获疗法（BNCT）药物对硼苯丙氨酸（BPA）的作用靶点。本文描述了几种合成目标化合物的方法、它们的急性毒性研究以及在两种肿瘤模型中的体内肿瘤摄取研究。有前景的化合物[BHNHC(NH(CH)CH(NH)COOH)CH]*3HO表现出低毒性（LD在150至300 mg/kg范围内）和优异的溶解性，并且在实验室小鼠的实验性黑色素瘤中也显示出选择性摄取（注射后60分钟内T/N比值保持>3，在45分钟时T/N最大值为6.2±2.8）。

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