Ketenimines are versatile synthetic intermediates capable of performing novel transformations in organic synthesis. They are normally generated in situ due to their inherent instability and high level of reactivity. Herein, we report pyridine-stabilized ketenimine zwitterionic salts, which are prepared through click chemistry from readily accessible alkynes and sulfonyl azides. To demonstrate their synonymous reactivity to ketenimines, these salts have been utilized in a cascade sequence to access highly functionalized quinolines including the core structures of an antiprotozoal agent and the potent topoisomerase inhibitor Tas-103.

01 Jan 2019·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Lamellarin-inspired potent topoisomerase I inhibitors with the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one scaffold

Q3 · MEDICINE

Article

Author: Okazaki, Fumiyasu ; Natsui, Yuko ; Fukuda, Tsutomu ; Fujimoto, Masahiro ; Yoshida, Kenyu ; Nanjo, Yusuke ; Iwao, Masatomo ; To, Hideto ; Ishibashi, Fumito

A new class of topoisomerase I inhibitors containing the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one (abbreviated as BBPI) ring system have been developed based on structure-activity relationship studies of the cytotoxic marine alkaloid lamellarin D. The pentacyclic BBPI scaffold was constructed from N-tert-butoxycarbonylpyrrole by sequential and regioselective functionalization of the pyrrole core using directed lithiation, conventional electrophilic substitution, and palladium-catalyzed cross-coupling reactions. Further N-alkylation of the scaffold followed by selective deprotection of the O-isopropyl group produced a range of N-substituted BBPI derivatives. The BBPIs thus prepared exhibited potent topoisomerase I inhibitory activity in DNA relaxation assays. The activities of BBPIs were higher than those of lamellarin D and camptothecin; they showed potent and selective antiproliferative activity in the panel of 39 human cancer cell lines established by Japanese Foundation for Cancer Research. COMPARE analyses indicated that the inhibition patterns of the BBPIs correlated well with those of the known topoisomerase I inhibitors such as SN-38 and TAS-103. The water-soluble valine ester derivative exhibited antitumor activity in vivo against murine colon carcinoma colon 26. The activity was comparable to that of the approved anticancer agent irinotecan.

01 Jul 2009·Colloids and Surfaces B: BiointerfacesQ2 · ENGINEERING & TECHNOLOGY

Preparation and properties of inhalable nanocomposite particles for treatment of lung cancer

Q2 · ENGINEERING & TECHNOLOGY

Article

Author: Keiji Hirota ; Masahito Komuro ; Takumi Ohkoshi ; Keishiro Tomoda ; Kimiko Makino ; Ganeshchandra S. Sonavane ; Takehisa Nakajima ; Hiroshi Terada ; Kenji Kitazato

Nanoparticles have widely been studied in drug delivery research for targeting and controlled release. The aim of this article is application of nanoparticles as an inhalable agent for treatment of lung cancer. To deposit effectively deep the particles in the lungs, the PLGA nanoparticles loaded with the anticancer drug 6-{[2-(dimethylamino)ethyl]amino}-3-hydroxyl-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103) were prepared in the form of nanocomposite particles. The nanocomposite particles consist of the complex of drug-loaded nanoparticles and excipients. In this study, the anticancer effects of the nanocomposite particles against the lung cancer cell line A549. Also, the concentration of TAS-103 in blood and lungs were determined after administration of the nanocomposite particles by inhalation to rats. TAS-103-loaded PLGA nanoparticles were prepared with 5% and 10% of loading ratio by spray drying method with trehalose as an excipient. The 5% drug-loaded nanocomposite particles were more suitable for inhalable agent because of the sustained release of TAS-103 and higher FPF value. Cytotoxicity of nanocomposite particles against A549 cells was higher than that of free drug. When the nanocomposite particles were administered in rats by inhalation, drug concentration in lung was much higher than that in plasma. Furthermore, drug concentration in lungs administered by inhalation of nanocomposite particles was much higher than that after intravenous administration of free drug. From these results, the nanocomposite particle systems could be promising for treatment of lung cancer.

100 Deals associated with BMS-247615

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Indication	Highest Phase	Country/Location	Organization	Date
Colonic Cancer	Preclinical	JP	University Of occupation & Environmental Health Japan	01 May 2005
Glioblastoma	Preclinical	JP	University Of occupation & Environmental Health Japan	01 May 2005
Squamous Cell Carcinoma	Preclinical	JP	University Of occupation & Environmental Health Japan	01 May 2005
Neoplasms	Discovery	-	Taiho Pharmaceutical Co., Ltd.	-
Neoplasms	Discovery	-	Bristol Myers Squibb Co.	-

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