Synthesis and In Vitro Antiproliferative Activity of 11-Substituted Neocryptolepines with a Branched ω-Aminoalkylamino Chain

• Published in: Molecules (Basel, Switzerland) Vol. 22; no. 11; p. 1954
• Main Authors: Shaban, Elkhabiry, Świtalska, Marta, Wang, Li, Wang, Ning, Xiu, Fan, Hayashi, Ikuya, Ngoc, Tran Anh, Nagae, Sachie, El-Ghlban, Samah, Shimoda, Shiho, Gokha, Ahmed Abdel Aleem El, Sayed, Ibrahim El Tantawy El, Wietrzyk, Joanna, Inokuchi, Tsutomu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.11.2017; MDPI
• Subjects: Alkaloids - chemical synthesis; Alkaloids - chemistry; Alkaloids - pharmacology; aminoalkylamino-substituted; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antiproliferative activity; Antiproliferatives; BALB 3T3 Cells; Biological activity; Breast cancer; Carbon; Cell Line, Tumor; Chain branching; Chains; Chemistry; Chemistry Techniques, Synthetic; Cytotoxicity; Diamines; DNA topoisomerase (ATP-hydrolysing); Humans; indolo[2,3-b]quinolone; Inhibitory Concentration 50; Leukemia; Mice; Molecular Structure; Natural products; neocryptolepine; Quinoline; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; SAR study; Spectrum Analysis; Structure-Activity Relationship; Substitutes; indolo[2,3-b]quinolone; aminoalkylamino-substituted; SAR study; neocryptolepine; antiproliferative activity
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules22111954

Neocryptolepine, which is a kind of tetracyclic indoloquinoline alkaloid, exhibits the inhibition of topoisomerase II and shows antiproliferative activity. The present study describes the synthesis and antiproliferative evaluation of several neocryptolepine analogues carrying a branched, functionalized dibasic side chain at C11. These 2-substituted 5-methyl-indolo[2,3-b]quinoline derivatives were prepared by nucleophilic aromatic substitution (S Ar) of 11-chloroneocryptolepines with appropriate 1,2- and 1,3-diamines. Some of the 11-(ω-aminoalkylamino) derivatives were further transformed into 11-ureido and thioureido analogues. Many of the prepared neocryptolepine derivatives showed submicromolar antiproliferative activity against the human leukemia MV4-11 cell line. Among them, 11-(3-amino-2-hydroxy)propylamino derivatives and 2k were the most cytotoxic with a mean IC value of 0.042 μM and 0.057 μM against the MV4-11 cell line, 0.197 μM and 0.1988 μM against the A549 cell line, and 0.138 μM and 0.117 μM against the BALB/3T3 cell line, respectively.