7. Marine natural alkaloids as anticancer agents

Alkaloids are naturally occurring nitrogen containing biologically active heterocyclic compounds. Over the last few years, a large number of biologically important alkaloids with antiviral, antibacterial, anti-inflammatory, antimalarial, antioxidant and anticancer activities have been isolated from marine source. Present article summarizes the isolation and anticancer activity evaluation of natural marine alkaloids and their synthetic analogues that includes pyridoacridine, indole, pyrrole, pyridine, Isoquinoline, guanidine and steroidal alkaloids. Introduction Since ancient times nature has been a source of medicines to cure many deadly diseases. Majority of drugs in use today are either natural products (NP), their derivatives (ND), natural products mimics (NPD) or semisynthetic derivatives (SSD) [1-4]. In natural sources, plants, animals and microorganisms have been the main source of biologically important molecules. Ocean has been considered as the main source of medicines and during the past two decades thousands of compounds and their metabolites with several different type of biological activity such as antimicrobial, anti-inflammatory, antimalarial, antioxidant, anti HIV and anticancer activity have been isolated from marine microorganisms [5-12]. But till date only few anticancer drugs such as citarabine, Dedicated to Dr. DS Bhakuni and Prof. Deepak Pental Correspondence/Reprint request: Prof. Diwan S. Rawat, Department of Chemistry, University of Delhi New Delhi-110007, India. E-mail: [email protected] Deepak Kumar & Diwan S. Rawat 214 vidarabine etc have been commercially developed from marine compounds while several others are currently in different stages of clinical trials [13]. Over 18000 compounds have been isolated from marine source and approximately 150 compounds are cytotoxic against the different tumor cells [14,15]. Some of the prominent anticancer compounds which are in different stages of clinical trials include aplidine, ecteinascidin-734 (Yondelis), bryostatin-1, squalamine, dolastatin10, ILX651, and KRN7000 (α-galactosylceramide) [16]. The present article summarises the recent development in the area of marine alkaloids that includes pyridoacridine, indole, pyrrole, pyridine, isoquinoline, guanidine and steroidal alkaloids. 1. Pyridoacridine alkaloids Pyridoacridines are highly coloured marine natural products having polycyclic planar heteroaromatic 11H-pyrido[4,3,2,mn]acridine system (1) [17]. They are probably the largest class among marine alkaloids and are almost universally isolated from sponges, ascidians as well as from a mollusc and a coelenterate [18]. Pyridoacridine alkaloids show significant biological activity primarily cytotoxicity and certain specific biological properties viz. fungicidal and bactericidal properties, inhibition of topoisomerase II, anti HIV, intercalation of DNA property, Ca releasing activity, production of reactive oxygen species [19-22]. These activities depends upon the substitution pattern of the basic structure of pyridoacridine, therefore many synthetic analogues have also been synthesized keeping the basic skeleton of pyridoacridine in mind. The synthesis of these analogues and their biological activity evaluation revealed that in most of the cases cytotoxicity of the analogues has improved compared to the parent molecule [23, 24]. During the last few years, numerous additional compounds of this family were isolated; most of them are polycyclic with different substituents such as shermilamine, kuanoniamine, neoamphimedine, arnoamines and styelsamines. It has been observed that almost all the pyridoacridines shows promising cytotoxicity against different type of tumors. Therefore a great interest was developed to modify the pyridoacridine moiety for developing a new generation of therapeutic agents. The first review article on marine pyridoacridines alkaloids was published by Molinski in 1993 [25] followed by Ding et al. in 1999 [26]. The cytotoxicity of the compounds of this family is a manifestation of their DNA binding properties, topoisomerase II inhibition and the production of reactive oxygen species. Pyridoacridines vary structurally by attachment of different side chains or fusion of different rings to ring C of the basic structure (1) and less often to the acridine nitrogen. Halogen substitution in pyridoacridines is quite rare; even if it is present, then it is always bromine at C2 in ring A. Oxidation states of the rings are variable and in some cases ring D is partially saturated. Additional rings are Marine natural alkaloids as anticancer agents 215 often attached to ring C. Pyridoacridines can be divided into tetracyclic, pentacyclic, hexacyclic, heptacyclic and octacyclic alkaloids.