3248 Current Medicinal Chemistry, 2008, 15, 3248-3267 0929-8673/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Alkannins and Shikonins: A New Class of Wound Healing Agents V.P. Papageorgiou*, A.N. Assimopoulou and A.C. Ballis Laboratory of Organic Chemistry, Department of Chemical Engineering, Aristotle University of Thessaloniki, Greece Abstract: Alkannins and Shikonins (A/S) are chiral-pairs of naturally occurring isohexenylnaphthazarins. They are found in the external layer of the roots of at least a hundred and fifty species that belong mainly to the genera Alkanna, Lithospermum, Echium, Onosma and Arnebia of the Boraginaceae family. Their occurrence in Jatropha glandulifera, a member of the Euphorbiaceae, should be considered as an exception. Pharmaceutical formulations with wound healing properties based on A/S have been in the market for many years. Al- though their wound-healing, anti-inflammatory, antimicrobial, antioxidant, antithrombotic and antitumor properties have been extensively documented, significant insight into their specific molecular pathways and mechanisms was hindered until recently. With the establishment of viable synthetic and biosynthetic routes of A/S and the synthesis of specific derivatives that were discovered the last few years, the effects of those compounds in the molecular-cell biology of human tissues in health and disease have just started being explored in depth, revealing a new class of drugs that hold promise as the basis for many valuable therapeutic targets. In the recent years, a wealth of new information arising from research efforts, on the wound healing properties of A/S has been accumulated. In this paper we review the findings and advances on the molecular and biological properties of A/S that promote wound healing. Keyword: Quinones, alkannin, shikonin, natural products, antibacterial activity, anti-inflammatory activity, wound healing, ulcers, leprosy, leprotic ulcer. 1. INTRODUCTION Although the roots of Alkanna tinctoria (A.t.) and Lithospermum erythrorhizon (L.e.), which are the main sources of Alkannin (A) and Shikonin (S) (Figs. 1, 2) respec- tively, have been used for the treatment of wounds since ancient times, their use has faded away with time. Ironically, the use of Alkannin as a food colorant has survived to our days. Alkannin attracted the attention of chemists in the forties, when it was used for a short period as an analytical reagent with limited success [1-3]. OH OH OH O O 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 OH OH OH O O Fig. (1). The chiral pair Alkannin and Shikonin that possesses major biological activity. A/S and their derivatives (Table 1) are nowadays potent pharmaceutical agents exhibiting strong wound healing, anti- inflammatory and antimicrobial properties, while their anti- tumor activity has attracted much interest recently. The story of the enantiomeric naphthoquinone natural products A (1) *Address correspondence to this author at the Laboratory of Organic Chem- istry, Department of Chemical Engineering, A.U.Th., 541 24 Thessaloniki, Greece, Fax: +30 2310 996252; E-mail: vaspap@eng.auth.gr and S (2) can be traced back many centuries ago. In fact, the story comprises two subplots with remarkably parallel courses in Europe and the Orient, being united only in the 20th century. Fig. (2). Computer-generated molecular models of Alkannin (left) and Shikonin (right). In Europe, the S enantiomer, Alkannin (1) (Figs. 1, 2) is found mainly in the roots of the plant A.t. Tausch (Fig. 3a), also known as Anchusa tinctoria, and in common English as Alkanet [4]. The compound is a parent molecule of the deep red pigments that are easily extracted from the roots of the plant [5, 6]. It was probably the highly colored nature of Alkannin that first captured the attention of botanists. Its use as a dyestuff for fabrics almost certainly dates back in centu- ries BC [7]. Perhaps the first recorded use of A.t. roots is found in the works of the Greek doctor and philosopher Hippocrates (4th and 5th centuries BC) who described their