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

Najla Altwaijry,Nashwah G M Attallah,Mohamed El-Bahnsawye,Elkhabiry Shaban,Thanaa A El-Masry,Ibrahim E.-T El Sayed,Samah El-Ghlban,Hytham M A Ahmed,Elshaymaa I Elmongy,Asmaa I Bayomi,Rehab M Samaka

doi:10.3390/molecules26030754

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.

Highlights

Cancer is one of the biggest concerns in the modern health system.In 2018 new cancer cases were registered, and 9.5 million people died because of canc cer is considered one of the major causes of death worldwide, outnumbered o diovascular
The target molecules were prepared from methyl-1H-indole-3-carboxylate 1 and Nmethylaniline
Flow cytometry was used to further evaluate the effects of the indoloquinoline compounds modes-of-action to the cellular level, and we extended our studies on the cell cycle effects

Summary

Introduction

In 2018 new cancer cases were registered, and 9.5 million people died because of canc cer is considered one of the major causes of death worldwide, outnumbered o diovascular. Exploring new drugs to meet the needs sistant diseases still a hotconcerns topic in medicinal chemistry. Drug resistance, the present situation is alarming, and new drugs are urgently. Cancer is considered one of the major causes of death worldwide, outnumbered only by surmount current issues such as side effects. Potential of natural c resistant diseases is still a hot in medicinal chemistry. BecauseThe of the consequence of drug resistance, the present situation is alarming,by and new drugs are urgently needed to as new drug leads is clearly illustrated the discovery and development of t surmount current issues such as side effects.

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