Design and Synthesis of Holu‐7, a Quinazolinone Derivative With an Active Stereo Geometry and Polar 2,4‐Dihydroxyphenyl Group, as a Selective Anticancer Agent

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Abstract
Quinazolin‐4‐one scaffolds offer rich anticancer chemistry but often trade potency for selectivity. Building on a tubulin‐targeting lead ( MJ‐65 ), 12 new derivatives ( 26 – 37 ) were synthesized to dissect geometry–activity relationships and enhance the polarity of C2‐substituents. Cytotoxicity was profiled against cancerous (HCT116 and CAL27) and normal (FHC) cells. In silico studies employed CDOCKER against tubulin (PDB 5NJH), GROMACS for molecular dynamics (MD), and ProTox‐3.0 for toxicity estimation. The previously synthesized geometry‐matched pairs 21 – 25 were active at 10 μM. In contrast, their isomers 26 – 30 were largely inactive, revealing a configuration‐dependent binding mechanism. Optimizing polarity yielded Holu‐7 (compound 35 ; 2,4‐dihydroxyphenyl at the C2‐position), which exhibited sub‐50 nM IC 50 in HCT116/CAL27 cells and > 10 μM in FHC cells and induced robust G 2 /M arrest. Docking/MD supported stable vinca‐site engagement, with hydrogen bonds to ASP179/ASN206 and π‐stacking with TYR224. ProTox‐3.0 predicted a higher LD 50 and absence of major organ toxicities relative to MJ‐65 . This data indicates that configuration‐aware, polarity‐tuned design can deliver selective quinazolinone anticancer candidates; therefore, Holu‐7 merits further preclinical evaluation.
Funding Information
  • National Science and Technology Council (MOST 109‐2320‐B‐039‐024)
  • National Science and Technology Council (MOST 111‐2320‐B‐039‐047‐MY3)
  • National Science and Technology Council (MOST 110‐2320‐B‐182‐023‐MY3)
  • China Medical University (CMU113‐MF‐35)

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