Design, Synthesis, Molecular Modelling and Anticancer Activities of New Fused Phenanthrolines

Abstract

Three series of fused pyrrolophenanthroline derivatives were designed as analogues of phenstatin and synthesized in two steps starting with 1,7-phenanthroline, 4,7-phenanthroline and 1,10-phenanthroline, respectively. Two (Compounds 8a and 11c) of the four compounds tested against a panel of sixty human cancer cell lines of the National Cancer Institute (NCI) exhibited significant growth inhibition activity on several cell lines. Compound 11c showed a broad spectrum in terms of antiproliferative efficacy with GI50 values in the range of 0.296 to 250 μM. Molecular docking studies indicated that Compounds 8a and 11c are accommodated in the colchicine binding site of tubulin in two different ways.

Synthesis and Biological Screening of New Cyano-Substituted Pyrrole Fused (Iso)Quinoline Derivatives

“…Simple isoquinoline and quinoline analogues were accommodated in the colchicine binding site in two distinct orientation modes, dependent on base ring structure. Isoquinolines 3a – c roughly occupied the same space as phenstatin in the tubulin binding site regardless of second ring substituents, although in a flipped manner when compared to other heterocyclic compounds with pronounced anticancer activity [ 19 ]. Thus, the isoquinoline moiety overlapped with the trimethoxysubstituted ring of phenstatin, being stabilized exclusively through hydrophobic interactions with side chains mainly in the β subunit (βCys241, βLeu255, βLeu242, βAla250, βLeu248, αAla180).…”

“…Taking into account the abovementioned details, as well as our ongoing interest in developing new bioactive fused heterocycles [ 17 , 18 , 19 , 20 , 21 , 22 ], we present herein the design and synthesis of novel pyrrolo[1,2- a ]quinoline and pyrrolo[2,1- a ]isoquinoline derivatives which show great promise as anticancer agents. The compounds bear cyano- and 4-substituted phenacyl groups as substituents at the pyrrole ring.…”

Cytotoxic substituted indolizines as new colchicine site tubulin polymerisation inhibitors

“…Its biological properties are comparable to CA-4, currently investigated in clinical trials 16 , but in contrast to CA-4, Phenstatin has a greater pharmacological potential due to improved metabolic stability and requires an easier synthesis for large-scale production 17 . In the process of drug discovery, this kind of compounds are lead scaffolds for the development of improved bioactive analogues, and Phenstatin continues to be a source of inspiration for researchers in designing new potential anticancer drugs [18][19][20][21][22][23][24][25] .…”

“…In our continuous efforts 22 , 24 to discover more effective microtubule destabilising agents, we have applied a structural combination strategy to design and synthesise a new series of indolizine-based Phenstatin analogues and evaluated their anticancer activity. Thus, we considered unsubstituted indolizines (at the pyridine ring) (compounds C, Figure 1 ), as well as several pyridyl-substituted indolizines (compounds D, E, and F, Figure 1 ) in order to investigate a possible beneficial influence of this group to the binding properties of generated compounds due to the lone pair electrons in this moiety.…”

Synthesis and properties of new fused pyrrolo-1,10-phenanthroline type derivatives

“…As a continuation of our dedicated research focused on phenanthrolines fused systems [27][28][29][30] and as part of our concern in the field of biologically active compounds, [31][32][33][34][35] the purpose of our present study was to synthesize new 1,10phenanthroline derivatives having one of its N-atoms locked in order to ensure a potential bio-activity (by maintaining the rings coplanarity and reducing the toxicity due to N-atoms internal chelating propensity). Thus, we report herein the synthesis, structure, fluorescence and the in vitro antimicrobial evaluation of several new 1,10-phenanthroline derivatives.…”