Anti-Cancer Agents in Medicinal Chemistry, 2008, 8, 000-000 1 1871-5206/08 $50.00+.00 © 2008 Bentham Science Publishers Ltd. Acetylenic Anticancer Agents A. Siddiq 1, * and V. Dembitsky 2, * 1 Department of Pharmacology, Faculty of Pharmacy, University of Karachi, Karachi 75270, Pakistan and 2 Institute of Biomedical Chemistry, Moscow 119121, Russia Abstract: This review is a comprehensive survey of acetylenic anticancer agents obtained from living organisms. Acetylenic metabolites belong to a class of molecules containing triple bond(s). They are found in plants, fungi, microorganisms, and marine invertebrates. Al- though acetylenes are common as components of terrestrial plants, fungi, and bacteria, it is only within the last 30 years that biologically active polyacetylenes having unusual structural features have been reported from plants, cyanobacteria, algae, invertebrates, and other sources. Naturally occurring aquatic acetylenes are of particular interest since many of them display important biological activities and possess antitumor, antibacterial, antimicrobial, antifungal, phototoxic, HIV inhibitory, and immunosuppressive properties. There is no doubt that they are of great interest, especially for the medicinal chemistry, and/or pharmaceutical industries. This review presents struc- tures and describes cytotoxic activities of more than 300 acetylenic metabolites isolated from living organisms. Key Words: Acetylenic, polyacetylenes, antitumor, agents, cytotoxic, bacteria, cyanobacteria, algae, invertebrates, fungi, plants, corals, sponges, tunicates, carotenoids, lipopeptides, depsipeptides, fatty acids. INTRODUCTION Natural acetylenic compounds have been isolated from a wide variety of plant species, cultures of higher fungi, and marine inver- tebrates [1-8]. Many of them display important biological activities, namely antitumor, antibacterial, antimicrobial, antifungal, photo- toxic, and other related medicinal properties [9,10]. Currently, about half of all prescribed medicines are extracted or derived from terrestrial plants and microorganisms. Most of the synthetic drugs, it should be noted, were originally inspired by novel compounds discovered in terrestrial organisms [11-13]. Plants have been used worldwide for treatment of various human ailments since antiquity. Their use is still quite prevalent in developing countries in the form of traditional/folkloric medicine. Intensive chemical and pharmacological studies during the last five decades have led in many cases to validation of traditional claims and facilitated identification of the traditional medicinal plants and of their active principles. Biological activities of acety- lenes and related compounds from higher plants have been studied intensively in recent years and their activity in various organisms is now well documented. More than 1000 acetylenic metabolites have been isolated and identified from plants, fungi, microorganisms, and marine invertebrates [1-5,14-16]. In the past several decades, natural acetylenic compounds have been isolated from a wide variety of macro- and microalgal species, freshwater and marine cyanobacteria, and other aquatic organisms. Extensive pharmacological screening performed on aquatic species resulted in discovery of novel antitumor agents [1,5,6,17-19]. The purpose of this review is to summarize antitumor and cytotoxic properties of more than 300 acetylenic natural products, belonging to diverse structural classes, including peptides, aliphatic and cyclic polyketides, terpenes, steroids, carotenoids, and lipids. Naturally occurring metabolites possessing an acetylenic unit, as well as polyacetylenes, are of particular interest as many of them display important biological activities, namely antitumor, antibacte- rial, antimicrobial, antifungal, and others. Their structure and bio- logical activities, modes of action, and future prospects are dis- cussed. This paper is a comprehensive survey of acetylenic antican- cer agents that are deemed as naturally occurring. *Address correspondence to this author at the Department of Pharmacology, Faculty of Pharmacy, University of Karachi, Karachi 75270, Pakistan; E-mail: siddiq.afshan@gmail.com and Institute of Biomedical Chemistry, Moscow 119121, Russia; E-mail: devalery@gmail.com ANTICANCER PEPTIDE METABOLITES The ubiquitous tropical cyanobacterium Lyngbya majuscula is a prolific producer of bioactive metabolites, and approximately 30% of all natural products reported from marine cyanobacteria have been isolated from these species [20]. The plethora of structurally diverse secondary metabolites isolated from L. majuscula exhibits a variety of bioactivities including antifeedant, molluscicidal, antipro- liferative, and immunosuppressive properties. More than half of the known secondary metabolites of the species are either cyclic or linear lipopeptides, some of them having an acetylenic unit [20]. The linear lipopeptides named apramides A (1), B (2), and G (3) have been isolated from the cytotoxic fraction of L. majuscula collected at Apra Harbor (Guam) [21]. Apramide G showed cyto- toxic activity, with IC 50 values of 33 ng/mL and 11 ng/mL against KB and LoVo cells, respectively [22]. Four new metabolites have been isolated from L. majuscula collected at Boca del Drago Beach, Bocas del Toro, Panama. These compounds were assigned the triv- ial names dragonamide (4), pseudodysidenin, dysidenamide, and nordysidenin. Dragonamide exhibited cytotoxic activity against P- 388, A-549, HT-29, and MEL-28 cells (IC 50 > 1 μg/mL) [23]. The first total synthesis of dragonamide was recently reported [24]. Carmabin A (5), a linear lipotetrapeptide, was isolated from the n- BuOH extract of L. majuscula. Using the MRC-5 human embryonic lung cell line in the confluent and proliferating states (cytotoxicity assessment assay), curacin A and carmabin produced the following IC 50 values: 6.58 μg/mL (crude extract with curacin A), 0.98 μg/mL (fraction with curacin A), 0.003 μg/mL (pure curacin A); 4.8 μg/mL (crude extract with carmabin), 0.6 μg/mL (fraction with carmabin A), and 0.06 μg/mL (pure carmabin A) [25]. Marine depsipeptides are composed of hydroxy and amino ac- ids linked by amide and ester bonds, and many of them showed very promising biological activities, including anticancer, antibacte- rial, antiviral, antifungal, anti-inflammatory, anti-clotting and anti- antherogenic properties. Depsipeptides have shown the greatest therapeutic potential as anticancer agents [26]. A new depsipeptide, malevamide C (6), was isolated from the cyanobacterium Symploca laete-viridis, collected near the south shore of Oahu, Hawaii [27]. At a concentration < 2 μg/mL, this compound was found to be active against P-388, A-549, and HT-29 cancer cells. The malevamide contains some unusual amino and hydroxy acids and several methylated and dimethylated residues. Other unusual moieties include 3-amino-2-methylhexanoic acid and 3-amino-2-methyl-7-octynoic acid. Hexane and butanol extracts of S. hydnoides showed cytotoxic activity against HT-29 human colon cancer cells [27].