One‐Step Synthetic Access to Isosteric and Potent Anticancer Nitrogen Heterocycles with the Benzo[c]phenanthridine Scaffold

Abstract

A versatile one-step two-component cyclization to build new tetracyclic nitrogen heterocycles is described. Ortho-methylhetarenecarbonitrile components were condensed with aldehydes to access a large library of differently substituted ring systems. The heterocyclic core can be easily modified by variation of the position of the endocyclic nitrogen atom in the o-methylhetarenecarbonitrile substrate. The manner of the nucleophilic attack that leads to the condensation can be triggered by different electron-density distribution in the molecule induced by the position of the nitrogen atom. Taking this into account, there is an electronic preference that leads to either pyridophenanthrolines or the corresponding pyridoazacarbazoles as the main products. We demonstrate the high antitumor potential of some of our synthesized heterocycles, which is strongly dependent on the substitution pattern introduced through the aldehyde component. The position and number of endocyclic nitrogen atoms play an important role regarding cytotoxicity of the studied compounds.

A Dual Topoisomerase Inhibitor of Intense Pro‐Apoptotic and Antileukemic Nature for Cancer Treatment

“… Natural‐product‐inspired development of aza‐analogs of benzo[ c ]phenanthridines . R 1 =OH, R 2 =OCH 3 : fagaronine; R 1 –R 2 = OCH 2 O: nitidine; R 3 =variously substituted aryl or alkyl groups; R 4 =H, OH, NH 2 , or various hydrophilic sidechains.…”

“…To overcome these disadvantages, we synthesized aza‐analogs of benzo[ c ]phenanthridines (compounds 9 – 14 ) by using various o ‐methylhetarene carbonitriles, and the core system was systematically adapted and optimized for both physicochemical properties and cytotoxicity (Figure ) . Applying the concept of an aminoalkyl side chain linked to a planar core system to achieve DNA intercalation as well as anti‐topoisomerase activity, the pyrido[3,4‐ c ][1,9]phenanthroline P8‐D6 ( 19 ) was found to be by far the most potent derivative of our compound library.…”

“…[38,39] To overcome these disadvantages, we synthesized aza-analogs of benzo[c]phenanthridines (compounds 9-14)b yu sing various o-methylhetarene carbonitriles, and the core system was systematically adapted and optimized for both physicochemicalp roperties and cytotoxicity ( Figure 2). [39][40][41][42] Applying the concept of an aminoalkyl sidechain linked to ap lanar core system to achieveD NA intercalationa sw ell as anti-topoisomerase activity, [18] the pyrido[3,4-c] [1,9]phenanthroline P8-D6 (19)w as found to be by far the mostp otent derivativeo four compound library.C ompound 19 was accessible via as imple four-step synthetic protocol commencing with commercially availables tartingm aterials to form the 6-amino-11,12-dihydro derivative 17 in at wo-fold ring closure including one-pot synthesis (Scheme1). [39] Dehydrogenation with Pd/C followed by diazotation with NaNO 2 in acidic aqueous medium yielded 18.…”

11‐Substituted Benzo[c]phenanthridines: New Structures and Insight into Their Mode of Antiproliferative Action

“…The high variability of the substituent at position 11 along with the possibility to build up N‐containing heterocyclic structures with N‐functionalized o ‐methylheteroaryl carbonitriles underlines the broad applicability and importance of this cyclization in heterocyclic chemistry. Using the synthetic route developed in our research group, a large number of recently discovered aza‐substituted benzo[ c ]phenanthridine isosteres are accessible (Scheme ) . These are the 11‐substituted 6‐amino‐11,12‐dihydropyrido[3,2‐ c ][1,7]phenanthrolines 5 , the 11‐substituted 6‐amino‐11,12‐dihydropyrido[4,3‐ c ][1,8]phenanthrolines 6 , together with 6‐substituted 5,6‐dihydro‐11 H ‐pyrido[3,4‐ i ]‐3‐azarcarbazoles 7 , 11‐substituted 6‐amino‐11,12‐dihydropyrido[3,4‐ c ][1,9]phenanthrolines 8 , 6‐substituted 5,6‐dihydro‐11 H ‐pyrido[3,2‐ i ]‐1‐azarcarbazoles 9 , and 11‐substituted 6‐amino‐11,12‐dihydropyrido[2,3‐ c ][1,10]phenanthrolines 10 and 11‐substituted 6‐amino‐1‐aza‐11,12‐dihydropyrimido[5,4‐ c ][1,9]phenanthrolines 11 , recently derived heterocyclic ring systems, which could be readily obtained by variation of the nitrile component 1 , namely with nitriles 12 – 16 with heterofunctionalized analogous structures bearing the nitrogen atom at different positions (Scheme ) …”

“… Working the nitrogen atoms of the carbonitrile around the clock affords a plethora of hitherto unknown substituted scaffolds using Clement–Weide cyclization …”