Bioactivities Of Quindoline Derivatives

Quindoline-derivatives are a class of alkaloids which have been extensivelystudied. Many years of research indicates that Quindoline-derivatives with a wide rangeof biological activity, such as anti-tumor, anti-bacteria and anti-virus. In recent years,modification of products from natural source has attracted a lot of interest. Thebiological activity of objects with or without boric acid modification in this study wasevaluated and a big difference among various compounds was observed. Quindolinederivatives have excellent anti-tumor activity, while after the modification of boronicacid, their cytotoxicity declined extremely and they also started owning anti-virusactivity. This study provides new judgment data of structure-activity relationship.Over60quindoline-derivatives were determined in Lung cancer cell lines (A549,H1299) and colon cancer cell lines (HCT116, HT29). Corresponding IC50values weregained and many of them showed excellent cytotoxicity, besides that colon cancer celllines displayed more sensitive to these compounds. IC50values of I-3which was themost active compound were0.21μM,0.35μM and0.39μM respectively in HCT116,A549, H1299cell lines. In HT29cell line, the most efficient compound was C-1’withthe lowest IC50value-0.27μM. In the cytotoxic activity test, we found that there was asignificant correlation between the structure and biological activity. Briefly, compoundsmodified by boric acid had less cytotoxicity than parent compounds, and modified atmeta-position had an even lower activity than para-position.To further explore structure-activity relationship. We took advantage of thecharacter that quindoline-derivatives possessing fluorescence. Flow cytometry andconfocal microscopy were used to research mechanism of action in vivo. Found thatcompounds modified with different functional groups differed in the cell positioning.Concrete manifestation: modified compounds having boronic acid groups were difficultto enter the nucleus and mainly located at cell membrane and cytoplasm. On thecontrary, compounds without modification distributed homogeneously in the whole cell,which indicated that compounds entry into nucleus were not impeded. The former owes comparatively weaker cytotoxicity, for example the IC50values of A3(parentcompound), A3A (Para-position boronic acid modification) and A3B (Meta-positionboronic acid modification) as3representative compounds from group A are7.42μM,8.96μM and9.02μM, when they act on A549cell line for48h, while the values are4.71μM,5.64μM and9.70μM on HT29cell line, respectively, which is coincide withthe results of confocal experiment. Besides, the majority of these compounds aremodified with boronic acid in the form of phenylboronic acid. To prove that it is boronicacid make the change, not because of benzene ring, we designed a series compoundwith benzene ring and without boronic acid in Group C. And these compounds showsimilar cytotoxicities with their parent compounds, or even better. That is to say, thedecrease of cytotoxicities on quindoline compounds is caused by boronic acid group,not others.Combined with observations from confocal and flow cytometry, we hypothesizedthat the molecular mechanism of these quindoline-derivatives killing cancer cellsmainly due to the combination of compounds and DNA. When boronic acid wasintroduced, the compounds’ polarity was increased and they were no longer enteringinto cell nucleus and lead to reduced cytotoxic activity.In addition, antiviral activity studies were carried out in vitro, which proved thevalidity of the above speculation. In the research of immune activity to influenza virusin A549cell line, it was found that compounds modified with boronic acid mainlylocated at cell surface like a coating wrapped the cell and delayed the process of viralentry into cells.In this paper, cytotoxic activity of quindoline-derivatives and their parent wereevaluated through a variety of cancer cell lines and used flow cytometry and confocalmicroscopy to study the structure-activity relationship of compounds. Prove that thecytotoxicity of quindoline-derivatives was negative correlation to the number ofboronic acids. Research on immune activity to influenza virus corroborated ourhypothesis, furthermore the finding also expanded potential applications of such compounds and provided a guideline for future research and development of drugs.