Reviews 1053 Naturally Occurring Homoisoflavonoids and Their Pharmacological Activities Authors Li-Gen Lin1, Qian-Yu Liu 1,YangYe2 Affiliations 1 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, P.R. China 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China Key words Abstract BAPTA‑AM:1,2-bis(2-aminophenoxy)ethane-N,N, l" homoisoflavonoids ! N′,N′-tetraacetic acid l" phytochemistry Homoisoflavonoids, a special subclass of flavo- Bcl-2: B-cell lymphoma 2 l" biosynthesis noids, are rarely found in nature, mainly existing bFGF: basic fibroblast growth factor l" pharmacological activities in Fabaceae and Asparagaceae families and being BHA: butylated hydroxyanisole less common in Polygonaceae, Portulacaceae, BHT: butylated hydroxytoluene Orchidaceae, and Gentianaceae families. Until CAM: chorioallantoic membrane now, approximately 240 natural occurring homo- CD: circular dichroism isoflavonoids have been identified from roots, cGMP: cyclic guanosine 3′,5′-monophosphate barks, heartwood, bulbs, leaves, and seeds of the c-src: proto-oncogene tyrosine-protein ki- plants from the above mentioned families, which nase sarcoma have often been used in traditional medicine. Ho- CYP1A: cytochrome P4501A moisoflavonoids have been reported with a broad DPPH: 2,2-diphenyl-1-picrylhydrazyl range of bioactivities, including anti-microbial, ECD: electronic circular dichroism anti-mutagenic, anti-oxidant, immunomodulato- EMS: ethyl methanesulfonate ry, anti-diabetic, cytotoxic, anti-angiogenic, vaso- EP: efflux pump relaxant, and anti-inflammatory effects. To or- ERK1/2: extracellular regulated protein ki- ganize this review, the homoisoflavonoids were nases 1/2 classified into five groups based on their struc- F-2,6-BP: fructose-2,6-bisphosphate tures: sappanin-type (I), scillascillin-type (II), bra- F-6-P: fructose-6-phosphate zilin-type (III), caesalpin-type (IV), and protosap- GLUT4: glucose transporter type 4 panin-type (V). The structures of natural occur- H-6-P: hexose-6-phosphate ring homoisoflavonoids are described, and their HTS: high-throughput screening received March 14, 2014 revised July 31, 2014 proposed biosynthetic pathway and recent phar- IC50: 50% inhibitory concentration accepted August 4, 2014 macological studies are discussed. The main pur- iNOS: inducible nitric oxide synthase pose of this review is to provide a comprehensive IL-2: interleukin 2 Bibliography This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. DOI http://dx.doi.org/ and up-to-date state of knowledge from phyto- IL-4: interleukin 4 10.1055/s-0034-1383026 chemical and pharmacological studies performed MIC: minimum inhibitory concentration Published online August 25, on homoisoflavonoids during the past decades. MMP-9: matrix metalloproteinase-9 2014 Homoisoflavonoids might have a large potential L-NAME: N(G)-nitro-L-arginine methyl ester Planta Med 2014; 80: for further investigations of their bioactivities in L-NMMA: N(G)-monomethyl-L-arginine acetate 1053–1066 © Georg Thieme Verlag KG Stuttgart · New York · order to identify important leads. LPS: lipopolysaccharide ISSN 0032‑0943 NO: nitric oxide NOS: nitric oxide synthase Correspondence 1 Dr. Li-Gen Lin Abbreviations ODQ: H-[1,2,4]oxadiazolo[4,3-a]quinoxa- State Key Laboratory of Quality ! lin-1-one Research in Chinese Medicine AAF: acetylaminofluorene p21: cyclin-dependent kinase inhibitor 1 Institute of Chinese Medical Sciences, University of Macau Akt: protein kinase B p53: tumor suppressor p53 Avenida da Universidade, Taipa AMPK: adenosine monophosphate-activated PDGF: platelet-derived growth factor 999078 Macau protein kinase PFK-2: 6-phosphofructo-2-kinase P.R. China Phone: + 85388228041 2AN: 2-aminoanthracene PI3-kinase: phosphatidylinositol 3-kinase [email protected] ATP: adenosine triphosphate Lin L-G et al. Naturally Occurring Homoisoflavonoids… Planta Med 2014; 80: 1053–1066 1054 Reviews PPARγ: peroxisome proliferator-activated receptor γ ROS: reactive oxygen species PTKs: protein tyrosine kinases VSMC: vascular smooth muscle cell Introduction bond in pyran ring, sappanin-type homoisoflavonoids could be ! further classified into six sub-groups: 3-benzylchroman type Homoisoflavonoids are a rather uncommon subclass of flavo- (Ia), 3-benzylchroman-3,4-diol type (Ib), 3-benzylchroman-4- noids which contain one additional carbon atom. They mostly one type (Ic), 3-benzylchroman-3-ol-4-one type (Id), Δ2,3 3-ben- are likely to originate from chalcone precursors. Up to now, about zylchroman-4-one type (Ie), and Δ3,9 3-benzylchroman-4-one 240 natural occurring homoisoflavonoids have been reported, type (If). Chemically, sappanin-type homoisoflavonoids can be distributed in various parts of plant materials. The homoisoflavo- easily cyclized and decyclized to form rearranged types, includ- noids isolated so far could be classified into five types based on ing scillascillin-type, brazilin-type, caesalpin-type, and protosap- their carbon skeleton: sappanin-type (I), scillascillin-type (II), panin-type [20,50]. Additionally, the attachment of hydroxyl, brazilin-type (III), caesalpin-type (IV), and protosappanin-type methoxyl, formyl and methyl groups to the framework and the (V). Sappanin-type homoisoflavonoids are further subdivided ac- configurations of the carbons on the pyran ring contribute to cording to the pyran ring moiety (l" Fig. 1). structural diversity as well. Sappanin-type homoisoflavonoids Since a wide range of biological and medicinal activities are at- account for a significant proportion of homoisoflavonoids. tributed to them, natural occurring homoisoflavonoids have been 3-benzylchroman type (Ia): Five 3-benzylchroman type homoiso- intensively studied in the past decades. In 2007, Abegaz et al. re- flavonoids ([1–5], l" Table 1) have been characterized from fami- viewed phytochemistry, biological activities, and synthesis of lies Fabaceae (Caesalpinia and Haematoxylum) and Asparagaceae homoisoflavonoids, but they did not classify the structural types (Dracaena and Agave). The hydroxyl groups can be found on C-5 of homoisoflavonoids appropriately [1]. In the past seven years, of ring A and C-4′ of ring B. Compounds 1–3 were identified with more than 70 homoisoflavonoids have been isolated and struc- a double bond at C-3 and C-4, while 4 and 5 were saturated at the turally elucidated, and various new pharmacological activities same positions and the stereochemistry of C-3 remained unre- related to homoisoflavonoids have been reported [2–36]. This re- solved. 3-benzylchroman type homoisoflavonoids are speculated view describes the structures of the homoisoflavonoids isolated to be byproducts of the biosynthesis of other molecules [20]. so far, discusses the biosynthesis of their different structural 3-benzylchroman-3,4-diol type (Ib): This sub-group consists of types and also summarizes the biological activities of naturally eighteen compounds (6–23, l" Table 1) that were identified from occurring homoisoflavonoids. plants of the Fabaceae family (Caesalpinia and Haematoxylum). The hydroxy or methoxy moieties are located at C-4. The hydrox- yl groups can be found on C-5 of ring A and C-4′ of ring B. The hy- Occurrence of Homoisoflavonoids droxyl group at C-3 is β-oriented in most compounds [15,20, 24, ! 35,48, 49] and α-oriented in only one compound (23) [15]. When Homoisoflavonoids are rarely found in nature, only existing in six the protons of the methylene (C-9) appear as singlet in the families so far. The majority of homoisoflavonoids have been 1H‑NMR spectrum, the relative configuration of the hydroxyl reported from Asparagaceae (Ophiopogon, Scilla, Muscari, groups on C-3 and C-4 is determined as cis; on the contrary, Polygonatum, Liriope, Agave, Chlorophytum, Hyacintus, Pseudo- when the methylene was shown as two doublets, the relative prospero, Drimia, Ornithogalum, Ledebouria, Dracaena, Chiono- configuration of the hydroxyl groups could be trans [15,20,24, doxa, Veltheimia, Bellevalia, Eucomis among others), and Fabaceae 35,48, 49]. The absolute configurations of C-3 and C-4 were de- (Hoffmannseggia, Caesalpinia, Cassia, Pterocarpus, Haematoxylum termined by CD spectroscopy. The negative Cotton effect at among others). Few homoisoflavonoids have been found in 283 nm suggested absolute configurations of C-3 and C-4 to be R Polygonaceae (Polygomum among others), Portulacaceae (Portu- and S, respectively; on the other hand, the positive Cotton effect laca among others), Orchidaceae (Cremastra among others), and at 283 nm indicated absolute configurations of C-3 and C-4 to be Gentianaceae (Tachiadenus among others) (l" Table 1 to 6). Ho- moisoflavonoids are widely distributed in different parts of plants, including roots, barks, heartwood, bulbs, leaves, and seeds. The greatest number of homoisoflavonoids (44 com- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. pounds) has been isolated from Ophiopogon japonicus [9,14, 17, 36–42], and a notable number has also been identified in the heartwoods of Caesalpinia sappanin [6,7,15, 18,24, 31,34, 43– 52]. All isoflavonoids are described based on their structural types. Structural Types of Homoisoflavonoids ! Sappanin-type (I) Sappanin-type homoisoflavonoids bear a 3-benzyl chromane skeleton, in which the benzopyran and aromatic rings are con- nected via one carbon. Until now, 191 sappanin-type