marine drugs Review Natural Products of Marine Macroalgae from South Eastern Australia, with Emphasis on the Port Phillip Bay and Heads Regions of Victoria James Lever 1 , Robert Brkljaˇca 1,2 , Gerald Kraft 3,4 and Sylvia Urban 1,* 1 School of Science (Applied Chemistry and Environmental Science), RMIT University, GPO Box 2476V Melbourne, VIC 3001, Australia; [email protected] (J.L.); [email protected] (R.B.) 2 Monash Biomedical Imaging, Monash University, Clayton, VIC 3168, Australia 3 School of Biosciences, University of Melbourne, Parkville, Victoria 3010, Australia; [email protected] 4 Tasmanian Herbarium, College Road, Sandy Bay, Tasmania 7015, Australia * Correspondence: [email protected] Received: 29 January 2020; Accepted: 26 February 2020; Published: 28 February 2020 Abstract: Marine macroalgae occurring in the south eastern region of Victoria, Australia, consisting of Port Phillip Bay and the heads entering the bay, is the focus of this review. This area is home to approximately 200 different species of macroalgae, representing the three major phyla of the green algae (Chlorophyta), brown algae (Ochrophyta) and the red algae (Rhodophyta), respectively. Over almost 50 years, the species of macroalgae associated and occurring within this area have resulted in the identification of a number of different types of secondary metabolites including terpenoids, sterols/steroids, phenolic acids, phenols, lipids/polyenes, pheromones, xanthophylls and phloroglucinols. Many of these compounds have subsequently displayed a variety of bioactivities. A systematic description of the compound classes and their associated bioactivities from marine macroalgae found within this region is presented. Keywords: marine macroalgae; bioactivity; secondary metabolites 1. Introduction The pharmaceutical industry has evolved as a result of research conducted in the areas of both synthetic organic chemistry and natural products extraction. During the period 1981–2014, approximately 42% of all U.S Food and Drug Administration (FDA) new drug approvals were based on either natural products or derivatives of a natural product pharmacophore [1]. Additionally, 49% of all anti-cancer drugs produced since the 1940s have been derived from a natural product source, or have been inspired by a natural product, and synthesized as a ‘natural product mimic’ [1]. Given the reduced effectiveness of traditional antibiotics to fight more resistant forms of bacterial infection in humans, together with the need for antibiotics in agriculture, there has been an increasing need to source new antibiotic drugs. Akin to this is the unabated need for bioactive compounds that show cytotoxic activity towards tumor cells for the effective treatment of cancers. This has provided much of the impetus for the research conducted within the field of natural product drug discovery, both from terrestrial and marine sources. While numerous drugs have been derived from terrestrial plants, there is still a huge untapped reserve of marine organisms that have been comparatively understudied. Terrestrial natural products (TNPs) have been exploited for their biological potency for many hundreds of years, whilst it is only recently, due to the increased use of SCUBA, that we have had access to the array of ocean-dwelling species, and this has led to an increase in the study of Marine Natural Products (MNPs). In fact, between 2014 and 2016, 203 new natural products were discovered from the study of macro algae (Green, Red and Brown) [2,3]. Many of these compounds displayed very Mar. Drugs 2020, 18, 142; doi:10.3390/md18030142 www.mdpi.com/journal/marinedrugs Mar. Drugs 2020, 18, 142 2 of 40 promising biological activity, making them serious contenders as anti-cancer and anti-bacterial drugs or drugMar. leads.Drugs 2020 A, 18 recent, 142 cheminformatics study has highlighted the potential of MNPs to2 of produce 39 drug-like chemical compounds [4]. Despite this, MNPs remain less studied than TNPs, mostly due to thepotential relative of ease MNPs with to whichproduce TNP drug-like specimens chemical can compounds be obtained [4]. and Despite cultivated. this, MNPs Currently, remain thereless are 10 FDA-approvedstudied than TNPs, marine-derived mostly due topharmaceutical the relative ease with drugs, which together TNP specimens with 30potential can be obtained candidates and for cultivated. Currently, there are 10 FDA-approved marine-derived pharmaceutical drugs, together application in a number of disease areas that are in different stages of clinical trials (Phase I, II and III) with 30 potential candidates for application in a number of disease areas that are in different stages Figureof1 clinical[5]. trials (Phase I, II and III) Figure 1 [5]. FigureFigure 1. Food 1. Food and and Drug Drug AdministrationAdministration (FDA)-approved (FDA)-approved and andPhase Phase III clinical III clinical drug candidates drug candidates derivedderived from from marine marine natural natural products. products. A numberA number of reviews of reviews have have also also detailed detailed thethe biolog biologicallyically active active natural natural products products that thatare sourced are sourced fromfrom marine marine organisms organisms [6 –[610–10],], highlighting highlighting marine organisms organisms as asan animportant important resource resource for the for the productionproduction of new of new and and unique unique compounds compounds withwith potentialpotential medicinal medicinal value. value. Many Many of the of compounds the compounds representedrepresented in Figurein Figure1 have 1 have been been isolated isolated from from sponges, sponges, ascidiansascidians and and cyanobacteria. cyanobacteria. Marine Marine macroalgae are underrepresented in the pharmaceutical pipeline despite the number of biologically macroalgae are underrepresented in the pharmaceutical pipeline despite the number of biologically active compounds. Marine algae have also been used in a number of other important areas including activethe compounds. food industry Marine [11], algaeagriculture have also[12] beenand usedas a insource a number of third-generation of other important bioplastics areas including[13]. the foodCompounds industry from [11], marine agriculture algae have [12] andbeen as shown a source to ex ofhibit third-generation a number of biologic bioplasticsally active [13 properties]. Compounds fromsuch marine as anti-microbial algae have been[6,7,14], shown anti-cancer to exhibit [15], aanti-leishmanial number of biologically [16], anti-inflammatory active properties [17], anti- such as anti-microbialfouling [18] [6 and,7,14 anti-protozoal], anti-cancer [19] [15 ],activities. anti-leishmanial Historically, [16 Australia], anti-inflammatory has been an excellent [17], anti-fouling source of [18] and anti-protozoalnovel marine invertebrate [19] activities. chemistry. Historically, Australia Australia has the largest has been Exclusive an excellent Economic source Zone (EEZ) of novel on the marine Mar. Drugs 2020, 18, 142 3 of 40 invertebrate chemistry. Australia has the largest Exclusive Economic Zone (EEZ) on the planet, which isMar. made Drugs up 2020 of several, 18, 142 diverse marine ecoregions. As a source of novel chemistry, Australia’s EEZ3 of 39 has been prolific, with its contribution representing the third largest of newly discovered MNPs during planet, which is made up of several diverse marine ecoregions. As a source of novel chemistry, the period 1965–2012, only behind Japan and China, respectively. Of interest is the marine ecoregion Australia’s EEZ has been prolific, with its contribution representing the third largest of newly of Port Phillip Bay, located on the south eastern coast of Australia in the state of Victoria. During discovered MNPs during the period 1965–2012, only behind Japan and China, respectively. 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