ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2012, Vol. 38, No. 3, pp. 328–334. © Pleiades Publishing, Ltd., 2012. 328 1 2 INTRODUCTION Human skin photoageing caused by exposure to sun results in origination of coarse wrinkles, discolor- ation, abnormal dermal pigmentation and loss of skin elasticity. Tissue connective components are degrad- able by the family of proteolytic enzymes, matrix met- alloproteinases including MMP-1, interstitial collage- nase. MMP-1 is found in a variety of cells, including fibroblasts, endothelial cells, smooth muscle cells, chondrocytes, and multiple tumor types [1]. The syn- ergistic action of MMP-1 with other MMP enzymes is responsible for degrading of skin collagen and elastin. In human skin, MMP-1, but not MMP-14 or MMP- 15, is highly induced by UV irradiation and appears to be responsible for collagen fragmentation associated with chronic sun exposure [2]. MMP-1 treatment of young skin in organ culture causes fragmentation of collagen fibrils, which reduces fibroblast stretch, consistent with reduced mechanical tension, as observed in aged human skin [3–5]. With 1 The article is published in the original. Abbreviations: MMP-1, matrix metalloproteinase-1; collage- nase-1; IL-8, Interleukin-8; DMEM, Dulbecco’s modified Eagle’s medium; FBS, fetal bovine serum; PBS, phosphate buffered saline; HaCaT cells, Immortalized human Kerati- nocytes. 2 Corresponding author: phone: 8-383-330-67-48; e-mail: kjwoong@hanyang.ac.kr, spopov@niboch.nsc.ru. aging the skin, collagen synthesis becomes lower and MMP-1 levels become higher even in sun-protected human skin [6]. Treatment of photo damaged skin with certain nat- ural chemicals, e.g., topical retinoids improves skin clinical appearance [7]. Retinoic acid (RA) is known to be a good suppressor of MMP-1 [8]. Terpenoids, flavonoids, and their accessible synthetic derivatives are of interest as components for human skin protec- tion. Derivatives of the lupane (betulin, betulinic acid), ursane (ursolic acid, UA), and oleanane series [9] were tested as suppressors of proteinases. Certain synthetic derivatives of triterpenoids were also exam- ined for MMP-1 inhibition [10]. Cytostatic and anti- proliferative activity was discovered for ursolic acid [11, 12], and more interestingly, it showed a mem- brane stabilizing effect [13]. Betulin derivatives were reported to have an ability to suppress UVB-induced MMP-1 expression [14]. Betulinic acid was found to inhibit stromelysin and collagenase effectively, while its analog, C-28 alcohol betulin, demonstrated lesser inhibition potency against these proteases [15]. Low toxicity and cytotox- icity levels, characteristic of betulin and its esters [16, 17], make them prospective as additives for skin protection. Certain flavonoids (sumaflavone and amentoflavone) have been demonstrated to reduce effectively the MMP-1 levels [18]. Study of Skin Anti-Ageing and Anti-Inflammatory Effects of Dihydroquercetin, Natural Triterpenoinds, and Their Synthetic Derivatives 1 Chan Woo Lee a , Nok Hyun Park a , Jin Woong Kim b , Byung Hun Um c , A. V. Shpatov d , E. E. Shults d , I. V. Sorokina d , and S. A. Popov d,2 a Amore-Pacific Co. R&D Center, 314-1, Bora-dong, Giheung-gu, Yongin-si, Gyeonggi-Do, 446-729, Republic of Korea b Dept. of Applied Chemistry, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 426-791, Republic of Korea c Natural Products Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute, Gangneung 210-340, Gangwon-do, Republic of Korea d Novosibirsk Institute of Organic Chemistry, Lavrentyev Ave. 9, Novosibirsk, 630090 Russian Federation Received May 16, 2011; in final form, June 1, 2011 Abstract—Accessible triterpenoids of ursane and lupane series, the flavonoid dihydroquercetin and their syn- thetic derivatives with polar substituents were tested in vitro for inhibition of collagenase 1 (MMP-1) in UVB irradiation assay. Ursolic acid and uvaol disuccinate were the most active inhibitors in the ursane series. In the lupane series, the best inhibition was manifested by carboxymethyl ester of betulonic acid and betulin succi- nates. Down- regulation of MMP-1 by dihydroquercetin and its synthetic derivatives surpassed the activity of a standard (retinoic acid). Keywords: collagenase-1, triterpenoids, dihydroquercetin, photoageing, interleukin-8 DOI: 10.1134/S1068162012030028