title: Synthesis and biological evaluation of deoxy-hematoxylin derivatives as a novel class of anti-HIV-1 agents.
abstract: SAR studies for the exploration a novel class of anti-human immunodeficiency virus type 1 (HIV-1) agents based on the hematoxylin structure (1) are described. The systematic deoxygenations of 1 including asymmetric synthesis were conducted to obtain a compound showing high potencies for inhibiting the nuclear import and viral replication as anti-HIV-1 agent. Among all, C-3-deoxygenated analog 16 exhibited most promising biological activities as anti-HIV-1 agent such as lower cytotoxicity (16:1; >80:40 μM), stronger inhibition of nuclear import (0.5:1.3 μM), and viral replication in HIV-1-infected TZM-bl cells (24.6:100 μM), human peripheral blood mononuclear cells (PMBCs) (30.1 μM: toxic). Different spectra of inhibitory activities against infected three healthy humans macrophages with high (donor A) and low (donor B and C) amounts of virus were also observed. Thus 16 showed 10-times stronger activity than 1 (16:1; 0.1:<1.0 μM) in the case of A, while 16 and 1 showed comparable activities in the cases of B and C (>0.01 and >0.00 1μM). The comparison of the inhibition of viral p24 antigen production was clearly indicated that compound 16 is at least twofold more potent anti-viral activity than 1. Thus, structures and actions of deoxy analogs particularly 16 could provide valuable information for the development of a novel class of anti-HIV-1 agents.
authors.affiliation: Molecular Imaging Medicinal Chemistry Laboratory, RIKEN Center for Molecular Imaging Science, 6-7-3 Minatoshima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ishii
authors.forename: Hiroko
authors.initials: H
authors.lastname: Koyama
authors.forename: Kyoji
authors.initials: K
authors.lastname: Hagiwara
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Miura
authors.forename: Guangai
authors.initials: G
authors.lastname: Xue
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Genta
authors.initials: G
authors.lastname: Kitahara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aida
authors.forename: Masaaki
authors.initials: M
authors.lastname: Suzuki
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006416:Hematoxylin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D010100:Oxygen; D006416:Hematoxylin