Preparation of Novel Homodimers Derived from Cytotoxic Isoquinolinequinones. A Twin Drug Approach.

Juana Ibacache,Jaime Valderrama,Margarita Montoya,Judith Faundes,Sophia Mejías

doi:10.3390/molecules23020439

Juana Ibacache, Jaime Valderrama + Show 3 more

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https://doi.org/10.3390/molecules23020439

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Abstract

The synthesis of five novel homodimers is reported based on the anilinoisoquinolinequinone scaffold. In these twin-drug derivatives, two units of the anilinoquinone pharmacophores are linked through a methylene spacer. The formation of dimers was achieved by reaction of isoquinolinequinones with 4, 4′-diaminodiphenylmethane via a sequence of two oxidative amination reactions. A preliminary in vitro screening of the homodimers reveals moderate to high cytotoxic activities against MDA-MB-21 breast adenocarcinoma and B16-F10 murine metastatic melanoma cell lines. The asymmetrical homodimer 15 stands out due to its cytotoxic potencies at submicromolar concentrations and high selectivity index (mean IC50 = 0.37 μM; SI = 6.97) compared to those of etoposide (mean IC50 = 3.67; SI = 0.32) and taxol (mean IC50 = 0.35; SI = 0.91) employed as reference anticancer drugs.

Highlights

The quinone nucleus is the common feature of many drugs used clinically in the therapy of solid cancers, such as daunorubicin, mitomycin, mitoxantrone, and saintopin
We have recently reported preliminary synthetic efforts aimed at the construction of homodimers of 7-anilinoisoquinolinequinones such as B and C, to produce twin drugs of these cytotoxic pharmacophores [12]
Work-up of the reaction mixture followed by column chromatography yielded product 6 and the symmetric homodimer 11 in 8 and

Summary

Introduction

The quinone nucleus is the common feature of many drugs used clinically in the therapy of solid cancers, such as daunorubicin, mitomycin, mitoxantrone, and saintopin. Among the broad variety of synthetic quinonoid compounds, a group of donor–acceptor members derived from 2-anilino-1,4naphoquinone and 7-anilinoisoquinoline-5,8-quinone analogues such as compounds A, B and C (Figure 1), have a wide range of remarkable in vitro cytotoxic activity against a variety of cancer cell lines [7,8,9,10,11]. We have recently reported preliminary synthetic efforts aimed at the construction of homodimers of 7-anilinoisoquinolinequinones such as B and C, to produce twin drugs of these cytotoxic pharmacophores [12]. The linkage of two identical pharmacophoric entities, generating an “identical twin drug” or homodimer derivative, is a classical strategy used in medicinal chemistry to produce more potent and/or selective drugs compared to the single entities [13,14,15,16]. The lack of reactivity of these amination products to undergo a further amination reaction with the isoquinolinequinones to give the corresponding homodimers is probably due to significant donor–

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