Antivascular and antitumor evaluation of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes, a novel series of anticancer agents

Abstract

A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as potent apoptosis inducers through a cell-based high throughput screening assay. Six compounds from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-116407, and MX-126303, were further profiled and shown to have potent in vitro cytotoxic activity toward proliferating cells only and to interact with tubulin at the colchicine-binding site, thereby inhibiting tubulin polymerization and leading to cell cycle arrest and apoptosis. Furthermore, these compounds were shown to disrupt newly formed capillary tubes in vitro at low nanomolar concentrations. These data suggested that the compounds might have vascular targeting activity. In this study, we have evaluated the ability of these compounds to disrupt tumor vasculature and to induce tumor necrosis. We investigated the pharmacokinetic and toxicity profiles of all six compounds and examined their ability to induce tumor necrosis. We next examined the antitumor efficacy of a subset of compounds in three different human solid tumor xenografts. In the human lung tumor xenograft (Calu-6), MX-116407 was highly active, producing tumor regressions in all 10 animals. Moreover, MX-116407 significantly enhanced the antitumor activity of cisplatin, resulting in 40% tumor-free animals at time of sacrifice. Our results identify MX-116407 as the lead candidate and strongly support its continued development as a novel anticancer agent for human use.

Green and Mechanochemical One-Pot Multicomponent Synthesis of Bioactive 2-amino-4H-benzo[b]pyrans via Highly Efficient Amine-Functionalized SiO2@Fe3O4 Nanoparticles

“…Keeping this background in mind, we proposed an ecofriendly grinding technology for the synthesis of 2-amino-4 H -benzo­[ b ]­pyrans using amine-functionalized silica magnetic nanoparticles (NH 2 @SiO 2 @Fe 3 O 4 ). In the last few years, tetrahydrobenzo­[ b ]­pyrans and its analogues have attracted great attention as they are part and parcel of various heterocyclic natural products and drugs that exhibit anticoagulant, antitumor, anticancer, antiallergic, diuretic, and antibacterial properties. − Additionally, they exhibit a broad spectrum of applications as cognitive enhancers that are used for treating neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, acquired immune deficiency syndrome (AIDS), and Down’s syndrome. , 4 H -benzo­[ b ]­pyran or chromene scaffold is found in several drugs that are pharmacologically active, for example, 2,7,8-triamino-4-(3-bromo-4,5-dimethoxyphenyl)-4 H -chromene-3-carbonitrile (A), 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-4 H -chromene-3-carbonitrile (B), ethyl-2-(2-amino-6-bromo-3-cyano-4 H -chromene-4-yl)-2-cyanoacetate (C), 2-amino-7-(dimethylamino)-4-(4-(dimethylamino)­naphthalene-1-yl)-4 H -chromene-3-carbonitrile (D), 2-amino-4-(furan-3-yl)-6,6-dimethyl-5-oxo-5,6,7,8-tetrahydro-4 H -chromene-3-carbonitrile (E), and 2-amino-6,6-dimethyl-5-oxo-4-(thiophen-3-yl)-5,6,7,8-tetrahydro-4 H -chromene-3-carbonitrile (F) shown in Figure . Because of the versatile utilization of substituted pyran analogues in medicinal chemistry, there is an upsurge to develop simple, inexpensive, and high yielding methods for their synthesis. , Our research group is focused on the design and synthesis of newer antimalarial drugs, single-crystal structure analysis, and catalysis of small molecules. − In continuation to this search, we had synthesized new and efficient economically benign catalyst NH 2 @SiO 2 @Fe 3 O 4 to optimize its efficacy in the synthesis of tetrahydrobenzo­[ b ]­pyrans.…”

White tea extract modified green synthesis of magnetite supported Ag nanoparticles: evaluation of its catalytic activity, antioxidant and anti-colon cancer effects

“…The scaffold has been found to construct the spine of an array of naturally occurring biomolecules and drugs. In addition, they demonstrate a wide spectrum of molecular activities like antibacterial, antiviral, antitumor, anticancer, antihypertensive, anticoagulant, anti-HIV, anti-infertility, antidepressant, anti rheumatic and several others [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62]. Despite the variety of competent catalytic methodologies reported in the synthesis of pyrano [3,2-c]chromene derivatives [63-77], there always remains abundant scopes for its further development.…”

Cesium-Carbonate-Mediated Benzalation of Substituted 2-Aryl-3-nitro-2H-chromenes with Substituted 4-Benzylidene-2-phenyloxazol-5(4H)-ones

“…Functionalized chromones are privileged scaffolds found in a wide variety of biologically active natural products and pharmaceuticals. − Among them, 2-aryl-3-nitro-2 H -chromenes have shown a number of biological properties, such as antiviral, antioxidant, antitumor, antimicrobial, and antiproliferative activities. They have also been recognized as important building blocks for the synthesis of natural products, pharmaceutical molecules, and functional materials. , For the functionalized reactions of 2-aryl-3-nitro-2 H -chromenes with a nitroolefin moiety, the nitro group of 3-nitro-2 H -chromene derivatives can be transformed into various functional groups to produce new derivatives .…”