Synthesis and Biological Activity of New Class of Dioxygenated Anticancer Agents

Abstract

This paper describes extensive research on the activity of more of 100 cytotoxic compounds containing an oxygenated ring in their structure and isolated from natural plants or prepared by semisynthesis or synthesis from available intermediates. Anticancer drugs have been classified according to the chemical structure of the natural products that are considered to lead the series. The origin and mechanism of action involved in each case have been considered. This new family of natural, semisynthetic and synthetic products includes compounds with interesting antitumor activity such as podophyllotoxin derivatives, NK-611 (15), TOP-53 (16), NPF (24) and Tafluposide (28); camptothecin analogs such as 45 with a considerable cytotoxicity against beta-cell chronic lymphocytic leukemia (CLL), and 52 (new piperazinyl-CPT analog). New dioxygenated ellipticine analogs showed more activity and stability than the natural pattern when the structure incorporated a lactone function instead of the pyridine ring. In the acridine series the new tetracyclic derivatives 75 and 76 containing ethylenedioxy groups at the 2- and 3-positions of the acridine system exhibited the same activity as m-AMSA in vivo against murine P-388 leukemia. Other isolated compounds containing a dioxygenated ring in their structure such as 100 and 101 showed antitumor activities related to kinase inhibition, and are attractive candidates for development of new synthetic antitumor agents.

Modeling the Antileukemia Activity of Ellipticine-Related Compounds: QSAR and Molecular Docking Study

“…Pharmacological data in vitro of several ellipticine analogues with antileukemia activity against L1210 cells were collected from the literature [40,41]. After the application of the Lipinski [42] rule filters, only 23 ellipticine analogues (ellipticine include) were selected.…”

“…It is necessary to mention that with the exception of ellipticine, the mechanisms of antileukemial cell proliferation inhibition by the compounds studied herein are not well known. One author proved that, in contrast to ellipticine, these kind of compounds are not able to inhibit topoisomerases I and II proteins [40,41]. In this regard, it seems that the antileukemial activity might be associated with other mechanisms that involve different targets than topoisomerases.…”

“…The data of in vitro ability to inhibit 50% L1210 leukemia cell proliferation for 23 ellipticine-related compounds were collected from the literature, mainly from Pujol et al [40] and Romero et al [41]. All data collection ensured homogeneity; all of the IC 50 data were obtained through the same experimental methods.…”

Recent Progress on C‐4‐Modified Podophyllotoxin Analogs as Potent Antitumor Agents

“…Today, PPT is still an effective and comparatively safe drug choice in the treatment of venereal warts. Besides antitumor effects, PPT analogs exhibit diverse activities, including reverse transcriptase (RT) inhibition and anti‐HIV activity; immunomodulatory activity; effects on the cardiovascular system; antileishmaniasis properties; 5‐lipoxygenase inhibition; insecticidal activity; phytogrowth inhibitory activity; ichthyotoxic activity; antimelanocortin‐4 receptor (MC4R) activity; and antirheumatic, antipsoriatic, antimalarial, and antiasthmatic properties …”

Naphthylnitrobutadienes as pharmacologically active molecules: evaluation of the in vivo antitumour activity

“…One of the most important goals of pharmacological research, to which great efforts are devoted worldwide, is the search for new molecular structures provided with effective antitumour activities, in particular effective against unresponsive tumours [1][2][3][4]. This is strictly linked to the significant increase of the incidence of cancer in the world in the last few years, together with the well known occurrence that an unacceptably high number of quite frequent tumour histotypes, in particular those of stomach, pancreas, colorectum, and lung, are still characterized by high mortality and unresponsiveness to the known anticancer drugs [5,6].…”