Pederine

Fig. 18 Pederin and related compounds from Paederus beetles...

The toxic effect of various species of rove beetles pertaining to the genus Paederus on the skin and eyes of mammals, including man, are due to the presence in their hemolymph of three vesicant amides pederin (104), pederone (105) and pseudopederin (106) (Fig. 18) [94,95], pederin being the major and most active of the three compounds. Their structure determination [96, 97] revealed rather unique substances until similar natural products with comparable biological activities were isolated from sponges of the genera Mycale [98,99], Stylinos [100] and Theonella [101-104]. 

Although many insect defensive compounds are endowed with diverse biological activities, few of them have been studied in depth to evaluate their potential pharmacological activities. Cantharidin (98) (Fig. 16),pederin (104) (Fig. 18), and some of the alkaloids isolated from ants (e.g., the solenopsins 109 and 110, Fig. 19) have been the subject of most of the investigations. These topics have been reviewed several times [111, 214,215], and we will only summarize here the most recent data. 

Pederin (104), the powerful cytotoxin of staphylinid beetles of the genus Paederus, has been the object of renewed interest due to the unexpected discovery of a series of closely related compounds in marine sponges that display antitumor activities. The latter, as well as pederin, were prepared by total synthesis and their biological activities were reported [219,220]. A recent review summarizing present knowledge on this family of compounds has been published [221]. 

It is doubtful whether the insect uses pederin for defensive purposes, because it acts on the skin of animals only when it is crushed and not through mere contact with the insect, even if prolonged. It also has neither insecticidal nor repellent properties (92). However, it causes epidermic necrotization as acute pederosis and desquamation as chronic pederosis on human skin. On the other hand, it stimulates bedsore cicatrization in lower doses and leads to complete healing. Application to mouse skin produces dermatitis with necrosis or huge edema, and the damaged tissue is reconstituted with a permanent loss of hair. 

Beside this dermatoxic activity pederin (147) has various biological activities (92). When administered in appropriate doses to partially hepatectomized rats, this compound stimulates development of hepatic tissues. The inhibitory effect at the cellular level has been found in chicken heart fibroblast cultures, and mice embryo, dog kidney, HeLa, and KB cell lines. In plants, root growth of Lupinus albus is inhibited and mitosis in Allium cepa blocked at the metaphasic stage. Also, pederin (147) inhibits protein synthesis and growth of yeast cells. In addition, the treatment of rat ascites sarcoma with purified extracts of P. fuscipes produces almost complete regression. 

Pseudopederin (148) and pederone (149) display the phytoinhibition, the dermotoxic, and toxic endoperitoneal action in mice, as well as the inhibitory activities on various animal and human cell strains. However, their effects are much less than those of pederin (147). Pederone (149) causes less endoperitoneal toxicity in vivo than the other two substances. 

Pederamide (512), an acid hydrolysis product of pederin (147) (467), has been synthesized by two research groups. In one approach (471) to 512, cw-di-methylbutyrolactone (513) was converted to the dihydroxyalkynyl ester (516) by... 

Many approaches to the synthesis of pederin have been tried (473,474). Total synthesis of (-l-)-pederin (147) was finally accomplished by two research groups (475-477) on the basis of a method joining pedamide, the right-hand half of pederin, and a pederic acid derivative, the left-hand half. 

Pedamide 536 was converted by treatment with trimethyloxonium tetrafluoro-borate to methyl pedimidate (549) (475), which was connected by the reaction sequence shown in Scheme 69 to (-l-)-acetylpederic acid (550), prepared via a route similar to that to the racemic pederamide (536) from (—)-(2/ ,3/ )-2,3-butanediol. The ratio of the resulting (-l-)-pederin (147) to (+)-10-epipederin (551) was 1 3. This ratio can be inverted to 60 14 by a stereocontrolled synthesis (476) including connection of methyl pedimidate (549) and (+)-selenoacid (552)... 

The synthesis of (-t-)-benzoylselenopederic acid (569) (477) (Scheme 71), the left-hand half of pederin (147), began with (-f-)-3-keto imide 570, which was subjected to the recently developed syn-directing Zn(BH4)2 reduction (482) to give 5yn-a-methyl-3-hydroxy acid derivative 571. Imide 571, after protection of the hydroxyl group as the THP ether, was reduced with DIBAH, and the resulting aldehyde was treated with lithium enolate of tm-butyl acetate to give the p-... 

Zn(BH4)2 reduction and phenylselenation. The methyl ester of 582 was selectively hydrolyzed hy PrSLi treatment to yield (-t-)-selenoacid (569) (Scheme 71). The total synthesis of (+)-pederin (147) from (-t-)-536 and (+)-569 was accomplished in a manner similar to Matsumoto s. 

Pederin (147) has been considered to be derived via polyketide biosynthesis, based on the result of feeding experiments with [ l- " C]acetate and [2- C]acetate in Paederus fuscipes (483). 

Pederin (735) is one of the most potent poisons known to man, with an LDso for rats of ca. 2 p.g per 100 g body weight. The pyran, which causes severe blistering of the skin, is part of the defence system of the beetle Paederus fuscipes. It inhibits chromosome division by first blocking protein synthesis and subsequently halting DNA synthesis. 

Psymberin (irciniastatin A), a cytotoxin of the pederin family, has been isolated from the marine sponges Psammocinia sp. and Ircinia ramosa. Its highly cytostatic... 

A copper(l)-catalyzed 1,4-addition of vinylmagnesium bromide to dihydropyran-4-one 1053 proceeds in good yield and with high diastereoselectivity to afford the tetrahydropyran-4-one 1054, a key intermediate during synthetic studies towards the pederin family of antitumour agents (Equation 411) <2000J(P1)2357>. 

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