Multigram scale synthesis of polycyclic lactones and evaluation of antitumor and other biological properties.

An efficient four-step synthesis of tetracyclic lactones from 1,4-benzodioxine-2-carboxylic acid was developed. Ellipticine derivatives exhibit antitumor activity however only a few derivatives without carbazole subunit have been studied to date. Herein, several tetracyclic lactones were synthesized and biologically evaluated. Several compounds (2a, 3a, 4a and 5a) were found to be inhibitors of the Kras-Wnt pathway. The lactone 2a also exerted a potent inhibition of Tau protein translation and was shown to have capacity for CYP1A1-bioactivation. The results obtained are further evidence of the therapeutic potential of tetracyclic lactones related to ellipticine. Molecular modeling studies showed that compound 2a is inserted between helix α3 and α4 of the KRas protein making interactions with the hydrophobic residues Phe90, Glu91, Ile9364, Hie94, Leu133 and Tyr137and a hydrogen bond with residue Arg97.

Substituted tetrahydroisoquinolines: synthesis, characterization, antitumor activity and other biological properties.

This work deals with the molecular design, synthesis and biological activity of a series of tetrahydro[1,4]dioxanisoquinolines and dimethoxyisoquinoline analogues. This study describes the synthesis strategy of these potential antitumor compounds, their multi-step synthesis and their optimization. A series of tetrahydroisoquinolines was synthesized and their cytotoxicity evaluated. Some of these tetrahydroisoquinolines showed promising KRas inhibition, antiangiogenesis activity and antiosteoporosis properties. Molecular modeling studies showed that compound 12 bind in the p1 pocket of the KRas protein making interactions with the hydrophobic residues Leu56, Tyr64, Tyr71 and Thr74 and hydrogen bonds with residues Glu37 and Asp38.

Synthesis and structure-activity relationships of new benzodioxinic lactones as potential anticancer drugs.

A set of disubstituted tetracyclic lactones has been synthesized and tested for potential antitumor activity. Several of them possess a noticeable cytotoxicity against L1210 and HT-29 colon cells in vitro. Relationships between chain nature and biological properties were sought. Lactones with a pentyl or hexyl substituent at C-11 are the most active ones. The introduction of a functional group at the side chain of C-11 modified the potency; carboxylic acid and primary amine decreased the cytotoxicity, whereas a cyano group increased the activity. An extensive structure-activity relationship study of these derivatives, including carbon homologues and bioisosteres has been performed. The synthesis and cytotoxicity of these compounds are discussed. Two lactones are recognized as potential lead compounds.

Synthesis and biological activity of new class of dioxygenated anticancer agents.

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.