Synthesis, Structure−Activity Relationships, and Antitumor Studies of 2-Benzoxazolyl Hydrazones Derived from Alpha-(N)-acyl Heteroaromatics

Abstract

Recently we have described the antitumor activities of 2-benzoxazolylhydrazones derived from 2-formyl and 2-acetylpyridines. In search of a more efficacious analogue, compounds in which the 2-acetylpyridine moiety has been replaced by 2-acylpyridine and alpha-(N)-acetyldiazine/quinoline groups have been synthesized. The 2-acylpyridyl hydrazones inhibited in vitro cell proliferation in the nM range, whereas the hydrazones derived from the alpha-(N)-acetyldiazines/quinolines inhibited cell growth in the muM range. Compounds tested in the NCI-60 cell assay were effective inhibitors of leukemia, colon, and ovarian cancer cells. E-13k [N-benzoxazol-2-yl-N'-(1-isoquinolin-3-yl-ethylidene)-hydrazine] inhibited the proliferation of MCF-7 breast carcinoma cells more efficiently than nontransformed MCF-10A cells. It is not transported by P-glycoprotein and a weak MRP substrate. Increased concentrations of serum or alpha(1)-acid glycoprotein did not reduce the antiproliferative activity of the compound. In the in vivo hollow fiber assay, E-13k achieved a score of 24, with a net cell kill of OVCAR-3 (ovarian) and SF2-95 (CNS) tumor cells.

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

“…An extended analysis including compounds beyond the MMPs shown in Figure 8A confirms that chelators with an NNS or NNN donor set are significantly more toxic than the ONS chelators ( Figure 5B, C). The pIC 50 values measured in the sensitive and resistant cells are overall rather similar, confirming the lack of P-gp influence on the toxicity of these compounds ( Figure 5C and S8).…”

“…In the presence of the efflux pump inhibitor Tariquidar both resistance to Triapine and increased sensitivity to the MDR-selective compounds 1a and 1d are reverted to control levels measured in MES-SA cells. The fraction of IC 50 values obtained in P-gp negative vs. positive cells serves as a quantification of the MDR selective effect (selectivity ratio, SR). Figure 3D shows the SR values for the isatin-β-thiosemicarbazones 1a -1e.…”

“…Literature data suggest that the imino carbon of thiosemicarbazones [68], aroylhydrazones [51], arylhydrazones [13] and benzothiazoles [49,50] may be a sensitive position for finetuning the biological activity of these Schiff bases. The role of imino carbon methylation on the toxicity of the investigated compounds is also evident from the structure-activity matrix shown in Figure 4.…”

“…Similarly, the acetaniline TSC (2p) forms Cu(II) complexes with moderate antibacterial and antifungal activity [46]. Similar to TSCs, benzothiazoles are also able to form biologically active metal complexes and find application as antibacterial and antifungal [45,46,[100][101][102], as well as antitumor agents [45,49,50,54,103,104].…”

Synthesis and Spectroscopic Investigations of Schiff Bases Transition Metal Complexes of Copper(II), Cobalt(II) and Nickel(II)

“…These complexes show oxidase biometric catalytic activity, anticancer and antimicrobial activities [6][7][8][9][10][11]. The study of Schiff bases and their complexes has become a focal point of interest for chemists in recent years, not only for their several structural features, but due to their potential application in various fields [12][13][14][15].…”