Development of Newly Synthesized Chromone Derivatives with High Tumor Specificity against Human Oral Squamous Cell Carcinoma

Abstract

Since many anticancer drugs show severe adverse effects such as mucositis, peripheral neurotoxicity, and extravasation, it was crucial to explore new compounds with much reduced adverse effects. Comprehensive investigation with human malignant and nonmalignant cells demonstrated that derivatives of chromone, back-bone structure of flavonoid, showed much higher tumor specificity as compared with three major polyphenols in the natural kingdom, such as lignin-carbohydrate complex, tannin, and flavonoid. A total 291 newly synthesized compounds of 17 groups (consisting of 12 chromones, 2 esters, and 3 amides) gave a wide range of the intensity of tumor specificity, possibly reflecting the fitness for the optimal 3D structure and electric state. Among them, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (compound 22), which belongs to 3-styrylchromones, showed the highest tumor specificity. 22 induced subG1 and G2 + M cell population in human oral squamous cell carcinoma cell line, with much less keratinocyte toxicity as compared with doxorubicin and 5-FU. However, 12 active compounds selected did not necessarily induce apoptosis and mitotic arrest. This compound can be used as a lead compound to manufacture more active compound.

Re-Evaluation of Chemotherapeutic Potential of Pyoktanin Blue

“…When cytotoxic chemotherapy drugs are accidentally leaked at the injection site, they can cause multiple emergencies by local and systemic reactions [ 38 , 39 ]. Vesicants such as doxorubicin (classified as anthracycline) and melphalan (classified as alkylating agent) bind to DNA and induce the formation of blisters and/or cause tissue destruction, while irritants such as 5-FU (classified as antimetabolite) can cause pain at the injection site or along the vein [ 17 ]. Considering the high incidence of side effects of anticancer drugs, it is necessary to investigate the extent to which PB induces oral stomatitis and extravasation in comparison with anticancer drugs.…”

“…As for anticancer activity, PB induced cell death in oral precancerous cells through ROS production, suppressed the progression of DMBA-induced oral precancerous lesions [ 15 ], and prompted apoptosis in a human breast cancer cell line [ 16 ]. Although many anticancer drugs induce adverse effects, such as oral mucositis, peripheral neurotoxicity, and extravasation at the injection site [ 17 ], most of previous studies of PB do not present information of its chemotherapeutic index (safety margin), possible adverse effects, and comparative performance against appropriate antiviral and antitumor agents. In the present study, antitumor activity, neurotoxicity, and antiviral activity of PB were re-evaluated by chemotherapeutic indices and in comparison with appropriate positive controls in order to establish the most effective administration schedule of PB.…”

Tumor-Specificity, Neurotoxicity, and Possible Involvement of the Nuclear Receptor Response Pathway of 4,6,8-Trimethyl Azulene Amide Derivatives

“…TS was calculated by dividing the mean CC 50 (HGF + HPLF + HPC) by the mean CC 50 (Ca9-22 + HSC-2 + HSC-3 + HSC-4), using seven cell lines ((D/B) in Table 1 ) [ 15 ], or dividing the CC 50 (HGF) by the CC 50 (Ca9-22) [(C/A) in Table 1 ], using two cell lines derived from the gingival tissue [ 27 ]. Normal keratinocytes, which are highly sensitive to many anticancer drugs [ 13 , 28 ], were not used in this study.…”

Chromones: Privileged scaffold in anticancer drug discovery

“…Some of the important reaction which can be implemented for the synthesis of chromones include Baker‐Venkatamaran rearrangement, Claisen condensation, Kostanecki‐Robinson reaction, Vilsmeier‐Haack reaction, and Simonis reaction (Reis et al, 2017). Some synthetic schemes and final chromone analog are detailed in Figure 2 (Sugita et al, 2020). Recent literature reports application of synthetic methodologies having advantage of environment friendliness, high yield, shorter reaction time, and ease of use.…”