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Synthesis of indolo[4,3-bc]phenanthridine-6,11(2H,12H)-diones using the Schiff base-homophthalic anhydride cyclization reaction.

ABSTRACT: A novel indolophenanthridine ring system has been synthesized via the Schiff base-homophthalic anhydride cyclization followed by thionyl chloride-mediated dehydrogenation and intramolecular Friedel-Crafts acylation. This adds to the array of heterocyclic systems that are available through the cycloaddition reaction of imines with cyclic dicarboxylic acid anhydrides. The cytotoxicities of the indolophenanthridines were investigated in human cancer cell cultures, and the results documented significant antitumor activity in a variety of human cancer cell lines. This provides a new heterocyclic scaffold for anticancer drug design.

SUBMITTER: Elsayed MSA

PROVIDER: S-EPMC5646376 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Synthesis of indolo[4,3-bc]phenanthridine-6,11(2H,12H)-diones using the Schiff base-homophthalic anhydride cyclization reaction.

Elsayed Mohamed S A MSA Zeller Matthias M Cushman Mark M

Synthetic communications 20160916 23

A novel indolophenanthridine ring system has been synthesized via the Schiff base-homophthalic anhydride cyclization followed by thionyl chloride-mediated dehydrogenation and intramolecular Friedel-Crafts acylation. This adds to the array of heterocyclic systems that are available through the cycloaddition reaction of imines with cyclic dicarboxylic acid anhydrides. The cytotoxicities of the indolophenanthridines were investigated in human cancer cell cultures, and the results documented signifi ...[more]

PMID: 29056779

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Project description:The novel compounds NSC745885 and NSC757963 developed at our laboratory were tested against a panel of 60 cancer cell lines at the National Cancer Institute, USA, and a panel of 39 cancer cell lines at the Japanese Foundation of Cancer Research. Both compounds demonstrated selective unique multi-log differential patterns of activity, with GI50 values in the sub-micro molar range against cancer cells rather than normal cardiac cells. NSC757963 showed high selectivity towards the leukemia subpanel. Activities of both compounds strongly correlated to expression of NFKB1 and CSNK2B genes, implying that they may inhibit the NF-κB pathway. Immunocytochemical microscopy of OVCAR-3 cells showed clear cytosolic accumulation of the NF-κB p65 subunit following treatment. Western blotting showed dose dependent inhibition of the nuclear expression of the NF-κB p65 subunit with subsequent accumulation in the cytosol following treatment. Docking experiments showed binding of both compounds to the NF-κB activator IKKβ subunit preventing its translocation to the nucleus. Collectively, these results confirm the ability of our compounds to inhibit the constitutively active NF-κB pathway of OVCAR-3 cells. Furthermore, COMPARE analysis indicated that the activity of NSC757963 is similar to the antituberculosis agent rifamycin SV, this was confirmed by testing the antimycobacterial activity of NSC757963 against Mycobacterium tuberculosis, results revealed potent activity suitable for use in clinical practice. Molecular properties and Lipinski's parameters predicted acceptable bioavailability properties with no indication of mutagenicity, tumorigenicity, irritability and reproductive effects. Oral absorption experiments using the human Caco-2 model showed high intestinal absorption of NSC745885 by passive transport mechanism with no intestinal efflux or active transport mechanisms. The unique molecular characterization as well as the illustrated anticancer spectra of activity and bioavailability properties warrant further development of our compounds and present a foundation brick in the pre-clinical investigations to implement such compounds in clinical practice.

Dataset Information

Synthesis of indolo[4,3-bc]phenanthridine-6,11(2H,12H)-diones using the Schiff base-homophthalic anhydride cyclization reaction.

Publications

Synthesis of indolo[4,3-<i>bc</i>]phenanthridine-6,11(2<i>H</i>,12<i>H</i>)-diones using the Schiff base-homophthalic anhydride cyclization reaction.

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