In Vitro and In Vivo Antitumor Activity of Indolo[2,3-b] Quinolines, Natural Product Analogs from Neocryptolepine Alkaloid

Abstract

Neocryptolepine (5-methyl-5H-indolo[2,3-b] quinoline) analogs were synthesized and evaluated in vitro and in vivo for their effect versus Ehrlich ascites carcinoma (EAC). The analogs showed stronger cytotoxic activity against EAC cells than the reference drug. The in vivo evaluation of the target compounds against EAC-induced solid tumor in the female albino Swiss mice revealed a remarkable decrease in the tumor volume (TV) and hepatic lipid peroxidation. A noticeable increase of both superoxide dismutase (SOD) and catalase (CAT) levels was reported (p < 0.001), which set-forth proof of their antioxidant effect. In addition, the in vitro antioxidant activity of the neocryptolepine analogs was screened out using the DPPH method and showed promising activities activity. The histopathological investigations affirmed that the tested analogs have a remarkable curative effect on solid tumors with minimal side-effect on the liver. The study also includes illustrated mechanism of the antitumor activity at the cell level by flow cytometry. The cell cycle analysis showed that the neocryptolepine analogs extensively increase the aggregation of tumor cells in three phases of the cell cycle (G0/G1, S and G2/M) with the emergence of a hypo-diploid DNA content peak (sub-G1) in the cell cycle experiments, which is a clear-cut for the apoptotic cell population. Furthermore, the immunological study manifested a significant elevation in splenic lymphocyte count (p < 0.001) with the elevation of the responsiveness of lymphocytes to phytohemagglutinin (PHA). These results indicate that these naturally-based neocryptolepine alkaloids exhibit marked antitumor activity in vivo and represent an important lead in the development of natural-based anticancer drugs.

Synthesis of 8-Fluoroneocryptolepine and Evaluation for Cytotoxic Activity against AGS Cancer Cells

“…It can cause cell cycle arrest and induce cell apoptosis and has a good antioxidant effect. 23,24,26 However, our study suggested that neocryptolepine lacks potency and has poor selectivity. The cytotoxicity of neocryptolepine to gastric cancer AGS cells was weak, and it was also cytotoxic to normal cells.…”

Comprehensive review of α-carboline alkaloids: Natural products, updated synthesis, and biological activities

“…Therefore, these analogs may be used to treat many oxidation related diseases such as cancer, cardiovascular, and inflammation caused by oxidative stress (Altwaijry et al, 2021).…”

Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile

“…Indolobenzazepines and indoloquinolines are fused heterocyclic scaffolds, which have gained a considerable interest in the field of medicinal chemistry. − Indolo­[3,2- d ]­benzazepines or paullones (backbone A in Chart ), first synthesized in 1992, were discovered as potential inhibitors of cyclin-dependent kinases (Cdks) ,, with antiproliferative activity similar to that of flavopiridol, the first Cdk-inhibitor that reached clinical trials as an anticancer drug. Later, other possible targets have been identified, namely, sirtuins, , GSK3β, ,,, and mitochondrial malate dehydrogenase .…”