Bicyclic Basic Merbarone Analogues as Antiproliferative Agents.

Andrea Spallarossa,Matteo Lusardi,Chiara Caneva,Camillo Rosano,Marco Ponassi,Aldo Profumo

doi:10.3390/molecules26030557

Andrea Spallarossa, Matteo Lusardi + Show 4 more

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https://doi.org/10.3390/molecules26030557

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Abstract

Pyrimido-pyrimidine derivatives have been developed as rigid merbarone analogues. In a previous study, these compounds showed potent antiproliferative activity and efficiently inhibited topoisomerase IIα. To further extend the structure–activity relationships on pyrimido-pyrimidines, a novel series of analogues was synthesized by a two-step procedure. Analogues 3–6 bear small alky groups at positions 1 and 3 of the pyrimido-pyrimidine scaffold whereas at position 6a (4-chloro)phenyl substituent was inserted. The basic side chains introduced at position 7 were selected on the basis of the previously developed structure–activity relationships. The antiproliferative activity of the novel compounds proved to be affected by both the nature of the basic side chain and the substituents on the pyrimido-pyrimidine moiety. Derivatives 5d and 5e were identified as the most promising molecules still showing reduced antiproliferative activity in comparison with the previously prepared pyrimido-pyrimidine analogues. In topoisomerase IIα-5d docking complex, the ligand would poorly interact with the enzyme and assume a different orientation in comparison with 1d bioactive conformation.

Highlights

Topoisomerases (Topo) are essential enzymes for DNA replication that catalyze the alteration of DNA topology through transient DNA strand breakage [1,2]
A thin layer chromatography (TLC) system for routine monitoring the course of reactions and confirming the purity of analytical samples employed aluminum-backed silica gel plates (Merck DC-Alufolien Kieselgel 60 F254 ): CHCl3 was used as developing solvent, and detection of spots was made by UV light and/or by iodine vapors
The synthesis of compounds 3–6 represents an efficient strategy for the preparation of pyrimido-pyrimidine derivatives bearing different substituents at position 1, 3 and 6

Summary

Introduction

Topoisomerases (Topo) are essential enzymes for DNA replication that catalyze the alteration of DNA topology through transient DNA strand breakage [1,2]. On the basis of their ability to cut one or both strands of a DNA double helix, topoisomerases can be classified into type I (EC 5.99.1.2) and type II (EC 5.99.1.3) enzymes [3,4]. Type II topoisomerase (TopoII) enzymes represent validated molecular targets for clinically used antitumor drugs such as amsacrine, etoposide, doxorubicin and mitoxantrone [5]. TopoII targeting agents can be classified as poisons or catalytic inhibitors [8,9]. TopoII poisons (e.g., etoposide, amsacrine, and mitoxantrone) are able to stabilize the cleavage complex inducing DNA double strand breaks whereas the catalytic inhibitors (e.g., aclarubicin, novobiocin, suramin, ICRF-193) block a specific step of TopoII catalytic cycle (e.g., ATP binding) [10,11]

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