Synthesis and cytotoxic evaluation of novel indenoisoquinoline-propan-2-ol hybrids

• Published in: Tetrahedron letters 2016-01, Vol.57 (4), p.466-471
• Main Authors: Thi, Tham Pham, Decuyper, Lena, Quang, Tan Luc, The, Chinh Pham, Dang Thi, Tuyet Anh, Nguyen, Ha Thanh, Le Nhat, Thuy Giang, Thanh, Tra Nguyen, Thi, Phuong Hoang, D’hooghe, Matthias, Van Nguyen, Tuyen
• Format: Article
• Language: English
• Subjects: 2-Carboxybenzaldehyde; Cytotoxicity; Indenoisoquinolines; Phthalide; β-Amino alcohols
• ISSN: 0040-4039; 1873-3581
• DOI: 10.1016/j.tetlet.2015.12.045

[Display omitted] The synthesis of N-substituted indenoisoquinolines was performed by applying a two-step condensation between 2-carboxybenzaldehyde and phthalide, followed by treatment with various primary amines. N-allylindenoisoquinoline was subsequently selected as a substrate for hydroxybromination, providing 6-(3-bromo-2-hydroxy)indenoisoquinoline as a key intermediate for derivatization in the lactam side chain. In this way, a series of 6-(2-hydroxypropyl)indenoisoquinolines bearing various functional groups at the 3′-position were prepared, which can be considered as novel indenoisoquinoline-propan-2-ol hybrid molecules. Subsequent cytotoxic evaluation of 28 indenoisoquinolines against two human cancer cell lines (Hep-G2 and KB) demonstrated a moderate to high antiproliferative activity displayed by 11 indenoisoquinolines thus synthesized. In particular, the introduction of the 2-hydroxypropyl side chain was shown to be beneficial for the overall cytotoxic activity, pointing to the potential relevance of these novel indenoisoquinoline-propan-2-ol hybrids.