Introduction: Many anticancer drugs have been reported to cause serious side effects such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that among 291 chromone derivatives, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (compound A) showed the highest tumor-specificity against human oral squamous cell carcinoma (OSCC) cell lines, exceeding that of doxorubicin and 5-FU. In this study, newly synthesized 65 chromone derivatives were investigated for their TS and side effects. Method: The 50% cytotoxic concentration (CC₅₀) for four OSCC (Ca9-22, HSC-2, HSC-3, HSC-4), normal oral cells (gingival fibroblast, periodontal ligament fibroblast, pulp cell), oral epithelial cells (HOK, HGEP) and differentiated PC12 neuronal cells was determined from the dose-response curve. TS was calculated as the ratio of the mean CC₅₀ for normal cells to that for OSCC. Apoptosis was assayed by cell cycle analysis. Results and Discussion: Newly synthesized indolychromones，indole-aurone hybrids，capsaicin derivatives，6,7-styrylchromones，3-benzylidenechromanones showed much lower TS value than compound A. Compound A should much lower keratinocyte toxicity than doxorubicin and 5-FU. 20 h treatment of Ca9-22 with compound A induced plateau level of cytotoxicity and accumulation of subG₁ and G₂/M population. In silico study suggests the inhibition of compound A against the estrogen related receptor-alpha signaling pathway, that is identified as an adverse marker for breast cancer progression and poor prognosis.