Author: Nishiyama, Takashi ; Shimoyama, Sayumi ; Kurata, Yuhki ; Hibino, Satoshi ; Choshi, Tominari ; Shigenobu, Saori ; Fujita, Erina ; Hatae, Noriyuki ; Okada, Chiaki ; Ishihara, Yuhsuke

The O4-benzo[c]phenanthridine alkaloids exhibit potent antiproliferative activity against cancer cells, which is derived from their ability to inhibit of topoisomerase I and II. It has been reported that in the alkaloids a cationic quaternary ammonium atom, which results in resonance effects between ring A and B, is necessary for increased antiproliferative activity. These findings indicate the role of their substituents at ring A on inhibition of tumor cell proliferation. In the present study, we systematically assessed the cytotoxic activities of naturally occurring alkaloids and their derivatives containing various ring A substituents against two tumor cell lines, HCT-116 colon tumor cells and HL-60 promyelocytic leukemia cells. Among the cationic iminium alkaloids, which displayed more potent activity than the corresponding neutral derivatives, and the 7,8-oxygenated benzo[c]phenanthridine alkaloids, chelerythrine and NK109, exhibited stronger antiproliferative activity than the 8,9- and 9,10-oxygenated alkaloids. The activity of cationic iminium alkaloids could be correlated with the bond lengths of their ring A substituents and the electrostatic potentials of their ammonium molecules by DFT calculation.

18 Mar 2011·Organic LettersQ1 · CHEMISTRY

Formal Synthesis of Nitidine and NK109 via Palladium-Catalyzed Domino Direct Arylation/N-Arylation of Aryl Triflates

Q1 · CHEMISTRY

Article

Author: Lautens, Mark ; Larnaud, Florent ; Candito, David A. ; Blanchot, Mathieu

The use of aryl triflates as reaction partners in a palladium-catalyzed domino direct arylation/N-arylation provides a great advantage due to the availability of starting materials. Furthermore, it allows expedient access to biologically interesting benzo[c]phenanthridine alkaloids.

01 Jul 2005·Biochemical PharmacologyQ2 · MEDICINE

Identification of a drug target motif: An anti-tumor drug NK109 interacts with a PNxxxxP

Q2 · MEDICINE

Article

Author: Kengo Sakaguchi ; Kengo Morohashi ; Seiichi Saito ; Seiichi Tanuma ; Atsushi Yoshimori ; Ayako Yoshino ; Fumio Sugawara

The synthetic compound NK109 shows anti-tumor effects against a number of human cancer cell lines. The mechanism of action is thought to involve the inhibition of DNA topoisomerase II. However, NK109 also exhibits potent anti-tumor activities against doxorubicin-, cisplatin- and etoposide-resistant human cell lines. This paper describes target validation of NK109 using biotinylated NK109 and a T7 phage library screening procedure. Phage particles displaying an affinity for NK109 were isolated and the DNA sequence determined. The amino acid sequences of selected peptides, and the results of mutation experiments by alanine scanning, confirmed that the binding target motif of NK109 is PNxxxxP. In silico analysis of the interaction between NK109 and the peptide, by docking simulation and molecular dynamics, supported this conclusion. The PNxxxxP motif exists in the C2 domain of protein kinase Calpha. NK109 was confirmed to bind the C2 domain from surface plasmon resonance analysis. Furthermore, NK109 moderately inhibited protein kinase C activity in vitro. Our results show that the anti-tumor activity of NK109 stems from interactions with multiple protein targets.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	JP	Nippon Kayaku Co., Ltd.	-
Thrombosis	Phase 1	JP	Nippon Kayaku Co., Ltd.	-

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