Pharmaceutical Chemistry Journal Vol. 35, No. 9, 2001 MEDICINAL PLANTS THE CHEMISTRY OF PEPTIDE ERGOT ALKALOIDS. PART 1. CLASSIFICATION AND CHEMISTRY OF ERGOT PEPTIDES E. L. Komarova1 and O. N. Tolkachev1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 9, pp. 37 – 45, September, 2001. Original article submitted February 22, 2001. INTRODUCTION ring in both qualitative and quantitative composition of alka- loids. To the present, ergot strains were specially selected Ergot alkaloids is a group of natural biologically active that are capable of producing predominantly a single alkaloid compounds belonging, according to the general alkaloid or a certain group of alkaloids: ergotamine, ergotoxin, ergoc- classification, to the class of indole derivatives. Ergot alkalo- ristine, etc. [3, 4, 6, 16 – 27]. ids are found in largest amounts in the fungal species of Cla- Owing to a high biological activity and broad spectrum viceps genus, the most widely occurring source of these sub- of pharmacological effects, ergot alkaloids are of considerab- stances being purple ergot (Claviceps purpurea Fr. Tul.) le importance for medicine. These compounds are now obtai- [1 – 6]. Another well-known fungal species producing alka- ned both by methods of artificial parasitic cultivation on rye loids of the clavine series is Claviceps paspali [11, 14, 19 – 22, 25 – 30] and by saprophytic growth techni- [1, 3, 4, 6 – 8]. Ergot alkaloids are rarely encountered in hig- ques [31 – 35]. her plants; examples are offered by the Ipomoea genus of the The most widely known pharmacological effect of ergot Convolvulaceae family occurring in Central America alkaloids is the ability to induce uterine contraction. Ergot [4, 9, 10]. extracts were officially used for the first time in gynecology. The life cycle of ergot consists of three sequential stages, The best known drugs of this type are ergotamine and ergo- including the (i) conidial stage of sphacelia, (ii) sclerotium metrine. (resting stage), and (iii) sephalated stroma with perithecium. As the chemical structure and pharmacological properti- The alkaloids are obtained from ergot sclerotium called es of ergot alkaloids were studied, the scope of their applica- “spurred rye” (Secale cornutum)[4–6,11]. The ergot sclerotium contains up to 30 – 40% of fatty tion considerably expanded. Ergot alkaloids exhibit a comp- oils and up to 2% of alkaloids. The other components of scle- licated action upon the organism, which accounts for a varie- rotium are free amino acids, ergosterin, choline, acetylcholi- ty of possible therapeutic applications. Dihydroxy derivati- ne, betaine, ergothionine, uracil, guanidine, free aromatic ves of ergotoxin alkaloids produce a-adrenoblocking and and heterocyclic amines (tyramine, histamine, agmatine), “venotonic” action. These compounds are administered in and alkylamines (the natural representatives of which were cases of hypertension, cerebral vasospasms, peripheral circu- originally found in ergot). The outer shell of sclerotium con- lation disorders, etc. [36 – 39]. tains acid pigments belonging to anthraquinolinic acid deri- Many ergot alkaloids produce a more or less pronounced vatives, including orange-red (endocrocin, clavorubin) and dopaminergic effect. Specific dopamine agonists are 2-Br-a- light-yellow (ergochromes, ergochrysins). These pigments and 2-Br-b-ergocryptines, which influence the secretion of impart to the sclerotium shell the characteristic gray- hypophyseal anterior hormones and produce a hypotensive ish-brown-violet color [6, 12 – 15]. Also encountered are the action upon the CNS, sympathetic nerve endings, and smo- albino ergot strains incapable of producing pigments [16]. oth vascular muscles. The drug abergin (Russia) [36, 37] or Investigation of the wild-growing Cl. purpurea species parlodel (bromergon, bromocriptine mesylate) are used for revealed the existence of numerous geographic types diffe- the treatment of a wide spectrum of disorders, including ga- lactorrhea, acromegalia, mastites, prolactinomas, amenor- 1 All-Russia Research Institute of Medicinal and Aromatic Plants, Moscow, rhea, and infertility and for the suppression of lactation, Cus- Russia. hing’s disease, some hormonal tumors, etc. [1, 36 – 44]. 504 0091-150X/01/3509-0504 The Chemistry of Peptide Ergot Alkaloids 505 The ergot alkaloids are administered both separately and 8 O H C OH in numerous complex compositions [39]. At present, extensi- 9 7 12 D 9 8 ve investigations aimed at the selection of new ergot strains, 5 NH 13 10 11 6 D creation of new original domestic drugs based on ergot alka- A H 10 N CH C 3 14 4 loids, and development of the corresponding technologies 16 5 H 15 B 3 are in progress in the All-Russia Research Institute of Medi- NH O 1 2 cinal and Aromatic Plants. C OH I NH 8 II 9 CLASSIFICATION OF ERGOT ALKALOIDS 10 N CH 3 5 The structure of ergot alkaloids is built around a tetracyc- H lic ring system of ergoline (Fig. 1). Depending on the structu- re of ring D in the ergoline nucleus and the types of substitu- NH III ents at C8, all ergot alkaloids can be divided into three bioge- Fig. 1. The structural formulas of ergoline (I), lysergic acid (II), and netically related classes: clavine ergot alkaloids, simple paspalic acid (III). lysergic acid derivatives, and peptide ergot alkaloids (ergot peptides). The biosynthesis of ergot alkaloids is genetically controlled [1,4–6,32,41,45–52]. The classes of simple lysergic acid derivatives and pepti- by the presence of a double bond C8=C9. Paspalic acid is the de ergot alkaloids are based on the lysergic acid (LA) frag- nucleus in some ergot alkaloids of the clavine series and is ment (Fig. 1), the structure of which was elucidated in 1938. frequently employed as an initial compound in the synthesis The two classes are distinguished by the type of substituents of various LA derivatives. in the acid radical [1, 4,6–8,53]. The LA molecule posses- ses two centers of symmetry (C5 and C8, Fig. 1). The active LA form was assigned a stereoconfiguration of 8R : 5R. THE CHEMISTRY OF PEPTIDE ERGOT Thus, all the natural pharmacologically active argot alkaloids ALKALOIDS are derivatives of D-6-methyl-9,10-ergoline-8b-carboxylic This review addresses the chemistry of ergot peptides. acid, representing a series of left-hand rotation isomers [4,6–8,53–58]. This class includes both natural ergot alkaloids and their mo- In 1964, H. Kobel et al. [59] isolated paspalic acid from dified derivatives, ergot peptides isolated from saprophytic the Cl. paspali ergot species (Fig. 1), which differs from LA ergot cultures, and synthetic ergot alkaloids. TABLE 1. Classification of Peptide Ergot Alkaloids R2 Configu- –CH –C H –CH(CH ) –CH(CH )C H R1 3 2 5 3 2 3 2 5 ration Ergotamine Ergotaman Ergoxin Ergoxam Ergotoxin Ergotoxam b-Ergoannam at C8 group group group group group group group 1 –CH(CH3)2 Ergovaline [Ergovalam] Ergonine [Ergonam] Ergocornine Ergocornam – R Ergovalinine – Ergoninine – Ergocorninine – –S –CH2CH(CH3)2 a-Ergosine [a-Ergosam] a-Ergoptine [a-Ergoptam] a-Ergocryptine a-Ergocryptam a,b-Ergoan- R nam3 a-Ergosinine – a-Ergoptinine – a-Ergocryp- ––S tinine 2 2 –CH(CH3)C2H5 b-Ergosine [b-Ergosam] b-Ergoptine [b-Ergoptam] b-Ergocryptine b-Ergocryptam a,b-Ergoan- R nam3 b-Ergosinine – b-Ergoptinine2 – b-Ergocryptini ––S ne –CH2C6H5 Ergotamine [Ergotaman] Ergostine [Ergostam] Ergocristine Ergocristam – R Ergotaminine – Ergostinine – Ergocristinine – –S 3 3 3 –CH2CH3 Ergobine – Ergobutine – Ergobutinine ––R 2 –CH3 Ergoalanine ––––––R Notes. 1 Names in square brackets refer to ergot alkaloids suggested to exist; 2 synthetic ergot alkaloids; 3 ergot alkaloids isolated from saprophytic ergot cultures. 506 E. L. Komarova and O. N. Tolkachev 10' 9' id – ergocristam – was isolated in 1973 from an ergocristine R1 OH O 11' NH O 8' strain of Cl. purpurea. Note that, to the present, only ergo- C N H 2' 12' H 7' peptams of the ergotoxam group were isolated from natural 8 5' 9 3' 4' ergot [4, 64 – 66] (Table 2). The probability of existence of 7 O O 2 12 N CH H R this alkaloid type decreases with decreasing volume of radi- 3 13 10 1 5 H cal R , which is explained by the high lability of ergopep- 1 14 4 tams. The presence of a branched radical R (Fig. 2, Table 1) 3 10' favors the formation of a more stable configuration of the tri- NH IV 1 9' 2 R 1 O H O 11' NH 8' peptide group in lactam alkaloids. In 1995, we obtained a C C N H 2' 12' H 7' mutant sclerotium of the ergocryptine Cl. purpurea strain N 5' 9 8 [67], which gave a progeny with genetically fixed biosynthe- 7 O 3' 4' O 2 12 N CH H R sis of the lactam ergot alkaloid ergocornam (Table 1). 3 13 10 5¢ 5 H In 1984, unusual C -epimers of lactam alkaloids were 14 4 isolated from a saprophytic culture of the ergocryptine ergot 3 NH species, which opened a new group of ergot alkaloids called 1 2 V b-ergoannams. It should be noted that ergot alkaloid derivati- Fig. 2. The structural formulas of classical peptide ergot alkaloids: ves untypical of natural ergot are frequently found in saprop- ergopeptines (IV) and lactam ergot alkaloids – ergopeptams (V). hytic cultures. Examples are offered by 12¢-O-methyl deriva- tives of ergocornine and a-ergocryptine (Table 2), 8-hydro- xyergotamine, and some other alkaloids [34, 77]. Peptide ergot alkaloids contain the LA fragment and a In attempts to obtain more active analogs of the natural tripeptide group (Fig. 2), the structure of the latter group de- ergot alkaloids, a large number of derivatives were synthesi- termining classification of the ergot peptides (Table 1). The zed by modifying both the LA fragment and the peptide part LA fragment is responsible for the basic biological activity of the molecule [1, 35, 68].