Discovery of a Potent Anticancer Agent PVHD303 with in Vivo Activity

Abstract

As a part of our continuous structure–activity relationship (SAR) studies on 1-(quinazolin-4-yl)-1-(4-methoxyphenyl)­ethan-1-ols, the synthesis of derivatives and their cytotoxicity against the human lung cancer cell line A549 were explored. This led to the discovery of 1-(2-(furan-3-yl)­quinazolin-4-yl)-1-(4-methoxyphenyl)­ethan-1-ol (PVHD303) with potent antiproliferative activity. PVHD303 disturbed microtubule formation at the centrosomes and inhibited the growth of tumors dose-dependently in the HCT116 human colon cancer xenograft model in vivo.

Inducible mismatch repair streamlines forward genetic approaches to target identification of cytotoxic small molecules

“…PVHD121 and its more potent derivative, PVHD303, (Figure 2A) are quinazoline derivatives that compete for colchicine binding to tubulin and inhibit tubulin polymerization in vitro . 16,17 The cellular effects of these compounds, however, are thought to be distinct from colchicine, which has raised the possibility that there is an alternative cellular target. 17,18 Cells treated with relatively high concentrations of PVHD121 or PVHD303 have abnormal spindles and no microtubules, consistent with inhibition of tubulin polymerization.…”

“…However, at concentrations close to the anti-proliferative IC 50 of the respective compounds, cells exhibit a more specific defect in centrosome-specific micronucleation. 17,18 These differences could be explained by either a different binding mode or an alternative target, and the identification of compound resistant mutations using iHCT116 might help differentiate between these two possibilities.…”

Synthesis, Biochemical Characterization, and Theoretical Studies of Novel β-Keto-enol Pyridine and Furan Derivatives as Potent Antifungal Agents

“…Indeed, pyridine and furan derivatives have been recently reported to possess pharmacological potential as fungicidal, 6 , 7 anti-inflammatory, 8 , 9 antiviral, 10 , 11 antibacterial, 12 , 13 and even anticancer agents. 14 , 15 …”

“…In recent years, the fused heterocyclic compounds containing bridgehead nitrogen- or oxygen-donor atoms have attracted great interest due to their biological activities and chemical medicinal properties. Indeed, pyridine and furan derivatives have been recently reported to possess pharmacological potential as fungicidal, , anti-inflammatory, , antiviral, , antibacterial, , and even anticancer agents. , …”

“…Indeed, pyridine and furan derivatives have been recently reported to possess pharmacological potential as fungicidal, 6,7 anti-inflammatory, 8,9 antiviral, 10,11 antibacterial, 12,13 and even anticancer agents. 14,15 On the other hand, heterocyclic compound bearing β-ketoenol functionality has been a fruitful source of inspiration for pharmaceutical and medicinal industries due to their widespread potential biological activities and their versatile utility in the world of medicinal chemistry, 16,17 such as antioxidant, 18 anti-inflammatory, 19 anticancer, 20 and antifungal 21 activities. In this context, β-keto-enol functionality was found in numerous natural products such as the curcumin and its derivatives (Figure 1), which have spurred numerous studies in medicinal chemistry.…”