Synthesis and antiviral activity of helioxanthin analogues.
A series of natural product analogues based on helioxanthin (2), with particular attention to modification of the lactone ring and methylenedioxy group, were synthesized and evaluated for their antiviral activities. Among them, lactam derivative 18 and helioxanthin cyclic hydrazide 28 exhibited significant in vitro antiviral activity against hepatitis B virus (EC(50) = 0.08 and 0.03 microM, respectively). Compound 18 showed the most potent antiviral activity against hepatitis C virus (55% inhibition at 1.0 microM). Compound 12, an acid-hydrolyzed product of helioxanthin cyclic imide derivative 9, was found to exhibit broad-spectrum antiviral activity against hepatitis B virus (EC(50) = 0.8 microM), herpes simplex virus type 1 (EC(50) = 0.15 microM) and type 2 (EC(50) < 0.1 microM), Epstein-Barr virus (EC(50) = 9.0 microM), and cytomegalovirus (EC(50) = 0.45 microM). Helioxanthin lactam derivative 18 also showed marked inhibition of herpes simplex virus type 1 (EC(50) = 0.29 microM) and type 2 (EC(50) = 0.16 microM). The cyclic hydrazide derivative of helioxanthin 28 and its brominated product 42 exhibited moderately potent activities against human immunodeficiency virus (EC(50) = 2.7 and 2.5 microM, respectively). Collectively, these molecules represent a novel set of antiviral compounds with unique structural features.
Yeo
Hosup
H
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Li
Ying
Y
Fu
Lei
L
Zhu
Ju-Liang
JL
Gullen
Elizabeth A
EA
Dutschman
Ginger E
GE
Lee
Yashang
Y
Chung
Raymond
R
Huang
Eng-Shang
ES
Austin
David J
DJ
Cheng
Yung-Chi
YC
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects; D004149:Dioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006678:HIV / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017705:Lignans / Q000737:chemistry*; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D001572:Benzofurans; D004149:Dioxoles; D007783:Lactones; D017705:Lignans; D009281:Naphthalenes