New substituted 4H-chromenes as anticancer agents

Abstract

As a continuation of our efforts to discover and develop small molecules as anticancer agents, we identified GRI-394837 as an initial hit from similarity search on RGD and its analogs. Based on GRI-394837, we designed and synthesized a focused set of novel chromenes (4a–e) in a single step using microwave method. All five compounds showed activity in the nanomolar range (IC50: 7.4–640 nM) in two melanoma, three prostate and four glioma cancer cell lines. The chromene 4e is active against all the cell lines and particularly against the A172 human glioma cell line (IC50: 7.4 nM). Interestingly, in vitro tubulin polymerization assay shows 4e to be a weak tubulin polymerization inhibitor but it shows very strong cytotoxicity in cellular assays, therefore there must be additional unknown mechanism(s) for the anticancer activity. Additionally, the strong antiproliferative activity was verified by one of the selected chromene (4a) by the NCI 60 cell line screen. These results strongly suggest that the novel chromenes could be further developed as a potential therapeutic agent for a variety of aggressive cancers.

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

“…Expected compounds are obtained in short reaction times and in good to excellent yields (Scheme 22). Patil et al [122] have described a fast and efficient method to synthesize substituted chromenes 113 using MW-activation. The reaction was achieved in a single step by the cyclocondensation of 3-dimethylaminophenol (110), substituted naphthaldehydes 111 and malononitrile (112) with few drops of TEA and MW-irradiated at 150 °C for 5 min under pressure.…”

“…The reaction was achieved in a single step by the cyclocondensation of 3-dimethylaminophenol (110), substituted naphthaldehydes 111 and malononitrile (112) with few drops of TEA and MW-irradiated at 150 °C for 5 min under pressure. In a preliminar assay, several Patil et al [122] have described a fast and efficient method to synthesize substituted chromenes 113 using MW-activation. The reaction was achieved in a single step by the cyclocondensation of 3-dimethylaminophenol (110), substituted naphthaldehydes 111 and malononitrile (112) with few drops of TEA and MW-irradiated at 150˝C for 5 min under pressure.…”

Zinc Triflate Promoted General Synthetic Protocol for the Facile Construction of Chromenes and Pyrimidines Bearing N-Allyl Quinolone Nucleus

“…From last few decades these compounds are gaining increasingly importance due to their therapeutic and pharmacological properties. Fused chromenes compounds possesses wide spectrum of activities such as antibacterial [1], anticancer agents [2], anti-rhinovirus activity [3], antipyretic, analgesic, anti-inflammatory and antioxidant activities [4]. Pyrimidines are an important class of the heterocyclic compounds possesses various therapeutic and pharmacological properties, like anti-inflammatory and antimicrobial agents [5], anticancer agents [6], antitubercular and antimicrobial activities [7] and antimalarial activity [8].…”

Glioma: A Tale of Corticosteroids, Thiopurines and Proposed Novel AntiGlioma Small Molecules

“…More importantly, these compounds demonstrated very low activity in normal astrocytes compared to glioma cell lines, implying a potential benefit with least toxicity. Based on structure activity relationship, it appears that the substitution of electron withdrawal atom on D-ring and/or electron donor atom on C-ring resulted in an improvement of chromene potency [168].…”

“…Drs. Miller and Patil research groups used RGD and similar analogs to search online libraries for similar anti-tumor small molecules [168]. From the 2 hits obtained, GRI-394837, a chromene analog was subsequently investigated.…”