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

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.

New 2-Acetyl-3-aminophenyl-1,4-naphthoquinones: Synthesis andIn VitroAntiproliferative Activities on Breast and Prostate Human Cancer Cells

“…The cytotoxicity of the quinones was assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) reduction assays [ 29 ], according to Valderrama et al [ 30 ]. Briefly, adherent cells were detached by using trypsin/EDTA solution.…”

On the Reaction of 2-Alkanoylnaphthohydroquinones with Hydroxylamine: Access to Cytotoxic 2-(Hydroxyamino)-1,4-naphthoquinone and Their 3-(Hydroxyimino)alkyl Analogous

“…Aluminum foil 60F 254 was used for analytical thin layer chromatography. The acylbenzohydroquinones (2)(3)(4)(5)(6)(7)(8)(9)(10)(11) were prepared according to a previously reported procedure [12].…”

“…2-Acylated-1,4-benzo-and 1,4-naphthohydroquinones I and III (Figure 1) are of current interest by their use as synthetic building blocks for carbo-and heterocyclic compounds endowed with cytotoxic and antiproliferative effects in various human cancer cells, as well as antifungal activities [1][2][3][4][5][6][7][8]. The synthetic advantage of these acylhydroquinones [9][10][11][12][13][14] emerges from the coexistence of the hydroquinone and the ortho-hydroxyacylarene fragments in their structures.…”