推测具有电子亲和力的放射增敏剂和缺氧组织标志物：C3-氨基取代苯并三嗪二氧（BTDO）的合成及初步体外生物学特性研究。

Putative electron-affinic radiosensitizers and markers of hypoxic tissue: Synthesis and preliminary in vitro biological characterization of C3-amino-substituted benzotriazine dioxides (BTDOs).

机构信息

Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Avenue Edmonton, Alberta, T6G 1Z2, Canada.

Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Avenue Edmonton, Alberta, T6G 1Z2, Canada; Joint Appointment to Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.

出版信息

Eur J Med Chem. 2019 Mar 1;165:216-224. doi: 10.1016/j.ejmech.2019.01.009. Epub 2019 Jan 14.

DOI:10.1016/j.ejmech.2019.01.009

PMID:30684798

Abstract

INTRODUCTION

The redox characteristics of 1,2,4-benzotriazine-1,4-dioxides (BTDOs) make them potential radiosensitizing agents for hypoxic cells in solid human cancers. Tirapazamine (TPZ) is the most clinically tested BTDO radiosensitizer, despite its toxicity at effective doses. To date, no BTDOs have been developed as diagnostic markers of tissue hypoxia.

HYPOTHESIS

TPZ analogues with appropriate reporting groups can act as potential radiosensitizers and hypoxia selective diagnostics.

EXPERIMENTAL AND RESULTS

3-Chloro-1,2,4-benzotriazine 1-oxide was substituted at the C3 position to afford 3-(2-hydroxyethoxyethyl)-amino-1,2,4-benzotriazine-1-oxide, which was oxidized to 3-(2-hydroxyethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (HO-EOE-TPZ) or converted to 3-(2-tosyloxyethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (Tos-EOE-TPZ). Tos-EOE-TPZ was intended for use as a synthon for preparing 3-(2-azidoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (N-EOE-TPZ) and 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (I-EOE-TPZ). The logP values (-0.69 to 0.61) for these molecules bracketed that of TPZ (-0.34). Cell line dependent cytotoxicities (IC) in air were in the 10-100 μM range, with Hypoxia Cytotoxicity Ratios (HCR; IC-air/IC-hypoxia) of 5-10. LUMO calculations indicated that these molecules are in the optimal redox range for radiosensitization, offering cell-line-specific Relative Radiosensitization Ratios (RRSR; SER/OER) of 0.58-0.88, compared to TPZ (0.67-0.76).

CONCLUSION

The LUMO, IC, HCR and RRSR values of 3-(2-substituted ethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxides are similar to the corresponding values for TPZ, supporting the conclusion that these TPZ analogues are potentially useful as hypoxia-activated radiosensitizers. Further studies into their biodistributions in animal models are being pursued to determine the in vivo potential in hypoxia management.

摘要

简介

1,2,4-苯并三嗪-1,4-二氧化物（BTDOs）的氧化还原特性使它们成为实体人类癌症中缺氧细胞的潜在放射增敏剂。替拉扎胺（TPZ）是最具临床测试的 BTDO 放射增敏剂，尽管其在有效剂量下具有毒性。迄今为止，还没有 BTDO 被开发为组织缺氧的诊断标志物。

假设

具有适当报告基团的 TPZ 类似物可以作为潜在的放射增敏剂和缺氧选择性诊断剂。

实验和结果

3-氯-1,2,4-苯并三嗪 1-氧化物在 C3 位置取代，得到 3-(2-羟乙氧基乙基)-氨基-1,2,4-苯并三嗪-1-氧化物，将其氧化得到 3-(2-羟乙氧基乙基)-氨基-1,2,4-苯并三嗪-1,4-二氧化物（HO-EOE-TPZ）或转化为 3-(2-对甲苯磺酰氧基乙氧基乙基)-氨基-1,2,4-苯并三嗪-1,4-二氧化物（Tos-EOE-TPZ）。Tos-EOE-TPZ 旨在用作制备 3-(2-叠氮乙氧基乙基)-氨基-1,2,4-苯并三嗪-1,4-二氧化物（N-EOE-TPZ）和 3-(2-碘乙氧基乙基)-氨基-1,2,4-苯并三嗪-1,4-二氧化物（I-EOE-TPZ）的合成子。这些分子的 logP 值（-0.69 至 0.61）在 TPZ（-0.34）的范围内。在空气中依赖细胞系的细胞毒性（IC）在 10-100μM 范围内，缺氧细胞毒性比（HCR；IC-air/IC-hypoxia）为 5-10。最低未占据分子轨道（LUMO）计算表明，这些分子处于放射增敏的最佳氧化还原范围内，与 TPZ（0.67-0.76）相比，提供了细胞系特异性相对放射增敏比（RRSR；SER/OER）为 0.58-0.88。