Abstract B26: Design and synthesis of furoquinoline derivatives as potential drug candidates for the treatment of lung cancers.

Abstract

Abstract Quinoline moiety is present in many classes of biologically active compounds. Recently, we have synthesized certain quinolone, 2-phenylquinoline, 2-furanylquinoline, and 4-anilinofuro[2,3-b]quinoline derivatives for biological evaluations. Among them, 1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone (CIL-102) was the most potent with a mean GI50 value of 0.025 μM against the growth of nine types of cancer cells and therefore, was further evaluated on its effects of cell cycle distribution. Results indicated CIL-102 induces cell cycle arrest in G2/M followed by apoptosis. CIL-102 bounds to tubulin at a single site with a dissociation constant of 0.4 μM. An analysis of the modified Dixon plot suggested that CIL-102 competitively inhibited the binding of podophyllotoxin, a colchicine-binding site agent, to tubulin. However, some drawbacks such as lack of selective cytotoxicity, poor oral bioavailability, and poor water solubility exhibited by CIL-102 prompted us to search for newer derivatives. Through extensive structural optimization, the new lead compound named as CYW-1865 which possesses aminoalkoxyimino side chain, exhibited selective anticancer activity, higher oral bioavailability, and higher water solubility than that of CIL-102. Xenographic studies indicated the tumor size with CYW-1865 treated nude mice was significantly lower than control. Further evaluation in an orthotopic lung cancer model indicated that CYW-1865 can be absorbed readily through oral administration, distributed to lung tissue, and exhibited significant efficacy in inhibiting the growth of lung cancers. Strategies for design and synthesis of CYW-1865 and its further structural optimization will be presented. Citation Format: Cherng-Chyi Tzeng, Chih-Hua Tseng, Yeh-Long Chen. Design and synthesis of furoquinoline derivatives as potential drug candidates for the treatment of lung cancers. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B26.