In Vitro Inhibition of Hsp90 Protein by Benzothiazoloquinazolinequinones Is Enhanced in The Presence of Ascorbate. A Preliminary In Vivo Antiproliferative Study.

Jaime A Valderrama,David Ríos,Julio Benites,Giulio G Muccioli,Pedro Buc Calderon

doi:10.3390/molecules25040953

Jaime A Valderrama, David Ríos + Show 3 more

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https://doi.org/10.3390/molecules25040953

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Abstract

A series of benzo[g]benzothiazolo[2,3-b]quinazoline-7,12-quinones were prepared from 2-acylnaphthohydroquinones and 2-aminobenzothiazoles and were evaluated for their in vitro antiproliferative activity. After screening using the MTT reduction assay, their IC50 values were calculated on a panel of cancer cells (T24, DU-145, MCF-7). Current standard anticancer drugs were included as control, and their calculated IC50 values were 7.8 and 23.5 µM for 5-fluorouracil and tamoxifen, respectively. Non-cancer cells (AG1523) were included to assess cancer cell sensitivity and drug selectivity. Four members of the series, with IC50 values from 0.11 to 2.98 µM, were chosen for further assays. The selected quinones were evaluated regarding their effects on cancer cell proliferation (clonogenic assay) and on Hsp90 and poly(ADPribose)polymerase (PARP) protein integrity. The most active compound (i.e., 15) substantially inhibited colony forming unit (CFU) formation at 0.25 µM. In the presence of ascorbate, it induced an oxidative cleavage of Hsp90 but had no effect on PARP protein integrity. In an in vivo animal model, it discreetly increased the mean survival time (m.s.t.) of tumor-bearing mice. In light of these results, compound 15 represents a potential lead-molecule to be further developed.

Highlights

Many natural and synthetic compounds sharing the 1,4-naphthoquinone scaffold display a wide variety of biological activities [1]
The quinones employed in this study were prepared by heteroannulation between acylnaphthoquinones generated in situ from their respective naphthohydroquinones 1–6, and
According to the proposed mechanism for heterocycle heteroannulation [16], the reaction is initiated by attacking the NH2 group of the aminobenzothiazoles at the 3-position of the acylnaphthoquinones

Summary

Introduction

Many natural and synthetic compounds sharing the 1,4-naphthoquinone scaffold display a wide variety of biological activities [1]. Quinones having redox-cycling properties are endowed with potential anticancer activities [1,2,3,4,5,6,7,8,9] The rationale behind this is based on a particular ambivalence of cancer cells: they produce a large amount of reactive oxygen species (ROS), while they are generally deficient in antioxidant enzymes [10,11,12,13]. An ROS-generating system (i.e., quinone redox cycling) yields a huge amount of ROS that exceeds the antioxidant defense capacity, compromising their fine redox equilibrium In this context, we have induced the alteration of intracellular redox homeostasis of cancer cells by using redox-cycler quinones as a new strategy in the research and development of new antitumor drugs. Numerous quinone derivatives have been synthesized and assessed for their biological activity in order to optimize this redox-cycling approach [11,14,15,16]

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