Synthesis and Antitumor Activity of 3-Methyl-4-oxo-3,4-dihydroimidazo [5,1-d][1,2,3,5]tetrazine-8-carboxylates and -carboxamides

Dan Liu,Jian-Guo Yang,Lin-Xiang Zhao,Jie Cheng

doi:10.3390/molecules15129427

Dan Liu, Jian-Guo Yang + Show 2 more

Open Access

https://doi.org/10.3390/molecules15129427

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Abstract

Seventeen novel 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylate and -carboxamide derivatives were synthesized and evaluated for their growth inhibition in seven human solid tumor and a human leukemia HL-60 cell lines. Compound IVa showed more activity than the other compounds and the positive control temozolomide. In the presence of 40 μg/mL of IVa, the survival rate of all tested tumor cells was less than 10%. Esters displayed more potent antitumour activity than amides and temozolomide against HL-60 cells. These compounds also exhibited considerably enhanced water-solubility.

Highlights

Temozolomide (Temodar, 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide), was approved bythe U.S FDA to treat the patients suffering from glioblastoma and anaplastic astrocytoma in 1999
This DNA damage can be repaired by O-6-methylguanine-DNA methyltransferase (MGMT) expressed in some tumor cells, which is the primary mechanism of tumor resistance to alkylating agents, including temozolomide [3]
The improvement of water-solubility of the synthesized compounds compared with temozolomide was estimated by calculating the high performance liquid chromatography (HPLC) peak area ratios in CH3COOH-CH3COONa buffer with pH 3.6

Summary

Introduction

Temozolomide (Temodar, 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide), was approved bythe U.S FDA to treat the patients suffering from glioblastoma and anaplastic astrocytoma in 1999. Temozolomide is converted into 5-(3-methyl-1-triazeno)imidazole-4carboxamide (MTIC) through chemical degradation without enzymatic catalysis, whereas dacarbazine requires metabolic activation to generate the active form [1]. 5-aminoimidazole-4-carboxamide (ACI) and a methyldiazonium ion [2], and the latter attacks the guanine segment of a sequence of three or more guanines on DNA leading to DNA methylation of (Scheme 1). This DNA damage can be repaired by O-6-methylguanine-DNA methyltransferase (MGMT) expressed in some tumor cells, which is the primary mechanism of tumor resistance to alkylating agents, including temozolomide [3].

Chemistry

Antiproliferative activities

General

Biological activity assays

Solubility detection

Conclusions