Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity

Abstract

A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as apoptosis-inducing agents through our cell-based apoptosis screening assay. Several analogues from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-126303, and MX-116407, were synthesized and further characterized. MX-116407, a lead compound from this series, induced apoptosis with an EC50 of 50 nmol/L and inhibited cell growth with a GI50 of 37 nmol/L in T47D breast cancer cells. Treatment of cells with these analogues led to G2-M arrest, cleavage of essential proapoptotic caspase substrates, and induction of nuclear fragmentation. We identified these compounds as tubulin destabilizers with binding site at or close to the colchicine binding site. Compounds in this series were also active in drug-resistant cancer cell lines with a GI50 value for one of the analogues (MX-58151) of 2.5 nmol/L in paclitaxel-resistant, multidrug-resistant MES-SA/DX5 tumor cells. This series of compounds displayed high selectivity against proliferating versus resting cells. Interestingly, these compounds were shown to disrupt preformed endothelial cell capillary tubules in vitro and affect functional vasculature to induce tumor necrosis in vivo and are thus likely to work as tumor vasculature targeting agents. Among these compounds, MX-116407 showed capillary tubule disruption activity in vitro at concentrations well below the cytotoxic dose. In a separate study, we further characterized the antitumor efficacy and pharmacokinetic profile of this series of compounds and identified MX-116407 as a potent apoptosis-inducing agent with apparent activity as tumor vasculature targeting agent.

One-Pot Multicomponent Solvent-Free Synthesis of 2-Amino-4H-benzo[b]pyrans Catalyzed by Per-6-amino-β-cyclodextrin

“…4 H -Pyran and its derivatives occur frequently in numerous natural compounds, exhibiting important biological activities and wide applications in pharmaceutical use such as antiallergic, antitumor, and antibacterial agents. − Furthermore, these compounds exhibit unique pharmacological activities including treatment of human inflammatory TNF-mediated diseases, Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and Parkinson’s disease. , Moreover, functionally substituted 4 H -pyrans have played increasing roles in synthetic approaches to promising compounds in the field of medicinal chemistry. , For example, 2-amino-4 H -pyran derivatives bearing nitrile functionality exhibit potential applications in the treatment of psoriatic arthritis and rheumatoid arthritis, as well as in cancer therapy. − The 4 H -pyran ring can be transformed to pyridine systems, which relate to pharmacologically important calcium antagonists of the dihydropyridine (DHP) type. , 2-Amino-3-cyano-4 H -pyrans possess photochemical activity . Because of their important use in organic synthesis, the synthetic methodologies for 4 H -pyran have been studied for many years.…”

Catalyst-Free [4+2] Cycloaddition of Ynamides with 2-Halomethyl Phenols To Construct 2-Amino-4H-Chromenes and α-Halo Enamides Simultaneously

“…The 2-amino-4 H -chromene skeleton belongs to the privileged structural motifs in numerous natural products as well as medicinal agents which exhibit diverse biological activities, including antitumor, antibacterial, antioxidative, and anti­hypertensive (Figure ). For instance, 2-amino-4-aryl-4 H -chromene (HFI-437) is a high-affinity inhibitor of insulin-regulated aminopeptidase, which has potential in the treatment of neurodegenerative disease . Compound MX 58151 was used as a tubulin inhibitor that binds at or close to the colchicine site of β-tubulin .…”

Facile and One-Pot Access to Diverse and Densely Functionalized 2-Amino-3-cyano-4H-pyrans and Pyran-Annulated Heterocyclic Scaffolds via an Eco-Friendly Multicomponent Reaction at Room Temperature Using Urea as a Novel Organo-Catalyst

“…2-Amino-3-cyano-4 H -pyrans are found to exhibit significant photochemical activity as well . Recently, a series of synthetic 2-amino-3-cyano-4 H -pyrans (Figure ) has been evaluated to possess potent anticancer, − antibacterial, antifungal, − and antirheumatic properties. Besides, the 4 H -pyran ring can be transformed to dihydropyridine (DHP) type systems having promising calcium antagonist properties. , Such a handful of diverse applications of 4 H -pyrans and pyran-annulated heterocyclic scaffolds in medicinal chemistry have drawn considerable interest during the last several years among synthetic chemists to develop useful synthetic routes to these heterocycles of potential interest; as a result, a good number of methods are already reported.…”