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Development of 3-methyl/3-(morpholinomethyl)benzofuran derivatives as novel antitumor agents towards non-small cell lung cancer cells.

ABSTRACT: As one of the most lethal malignancies, lung cancer is considered to account for approximately one-fifth of all malignant tumours-related deaths worldwide. This study reports the synthesis and in vitro biological assessment of two sets of 3-methylbenzofurans (4a-d, 6a-c, 8a-c and 11) and 3-(morpholinomethyl)benzofurans (15a-c, 16a-b, 17a-b and 18) as potential anticancer agents towards non-small cell lung carcinoma A549 and NCI-H23 cell lines, with VEGFR-2 inhibitory activity. The target benzofuran-based derivatives efficiently inhibited the growth of both A549 and NCI-H23 cell lines with IC₅₀ spanning in ranges 1.48-47.02 and 0.49-68.9 µM, respectively. The three most active benzofurans (4b, 15a and 16a) were further investigated for their effects on the cell cycle progression and apoptosis in A549 (for 4b) and NCI-H23 (for 15a and 16a) cell lines. Furthermore, benzofurans 4b, 15a and 16a displayed good VEGFR-2 inhibitory activity with IC₅₀ equal 77.97, 132.5 and 45.4 nM, respectively.

SUBMITTER: Al-Sanea MM

PROVIDER: S-EPMC8128204 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer, and the incidence and mortality rate are continuously increasing. In many cases, lung cancer cannot be completely treated with surgery, so chemotherapy is used in parallel; however, the treatment often fails due to drug resistance. Therefore, it is necessary to develop a new therapeutic agent with a new target. The expression of sphingosine kinase promotes cancer cell growth and survival and induces resistance to chemotherapeutic agents. Sphingosine-1-phosphate (S1P), produced by sphingosine kinase (SK), has been shown to regulate cancer cell death and proliferation. PF-543, currently known as an SK inhibitor, has been reported to demonstrate low anticancer activity in several cancers. Therefore, in this study, a derivative of PF-543 capable of increasing anticancer activity was synthesized and its efficacy was evaluated by using an NSCLC cell line and xenograft animal model. Based on the cytotoxic activity of the synthesized compound on lung cancer cells, the piperidine forms (Compounds 2 and 4) were observed to exhibit superior anticancer activity than the pyrrolidine forms of the head group (Compounds 1 and 3). Compounds 2 and 4 showed inhibitory effects on SK1 and SK2 activity, and S1P produced by SK was reduced by both compounds. Compounds 2 and 4 demonstrated an increase in the cytotoxicity in the NSCLC cells through increased apoptosis. As a result of using an SK1 and SK2 siRNA model to determine whether the cytotoxic effects of Compounds 2 and 4 were due to SK1 and SK2 inhibition, it was found that the cytotoxic effect of the derivative was SK1 and SK2 dependent. The metabolic stability of Compounds 2 and 4 was superior compared to PF-543, and the xenograft experiment was performed using Compound 4, which had more excellent MS. Compound 4 demonstrated the inhibition of tumor formation. The results of this experiment suggest that the bulky tail structure of PF-543 derivatives is effective for mediating anticancer activity, and the results are expected to be applied to the treatment of NSCLC.

Project description:Background and aimNon-small cell lung cancer (NSCLC) continues to claim millions of lives worldwide. Although its poor prognosis is largely attributed to the lack of adequate and precise detection technologies, cancer cells' suppression of the immune system adds on to the difficulty of identifying abnormal NSCLC tumors in their early stages. Therefore, cancer immunotherapy, which activates the immune system and helps it fight tumors, has recently become the most sought-after technique, especially in the advanced stages of NSCLC, where surgery or chemotherapy may or may not bring about the desired survival benefits in patients.MethodsThis review focuses on the various immunotherapeutic interventions and their efficacy in advanced NSCLC clinical trials. Monoclonal antibodies like anti-PD-1/PD-L1 agents and anti-CTLA-4 antibodies, cancer vaccines, oncolytic viruses and adoptive T cell therapy have been discussed in brief. Furthermore, the effects of gender, age, and race on the efficacy of immune checkpoint inhibitors and suggest plausible future approaches in the realm of immuno-oncology.ResultsImmunotherapy is used alone or in combination either with other immunological agents or with chemotherapy. However, the efficacy of these strategies depends extensively on various demographic variables, as some patients respond perfectly well to immunotherapy, while others do not benefit at all or experience disease progression. By targeting a "hallmark" of cancer (immune evasion), immunotherapy has transformed NSCLC management, though several barriers prevent its complete effectiveness.ConclusionsAll these immunological strategies should be interpreted in the current setting of synergistic treatment, in which these agents can be combined with chemotherapy, radiotherapy, and, or surgery following patient and tumor characteristics to proportionate the best-individualized treatment and achieve superior results. To better pursue this goal, further investigations on cost-effectiveness and sex-gender, race, and age differences in immunotherapy are needed.

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Development of 3-methyl/3-(morpholinomethyl)benzofuran derivatives as novel antitumor agents towards non-small cell lung cancer cells.

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