Structure‐activity relationships in allergic contact dermatitis

Abstract

Primin (2-methoxy-6-pentyl-1,4-benzoquinone) is a naturally-occurring strong sensitizer from Primula obconica (Primulacease). To determine the effect of side-chain length on sensitizing potency, 15 analogues with linear side chains from C1 to C15 and 4 C6-analogues with branched side chains were prepared synthetically and devoted to experimental sensitization in guinea pigs. The results showed an increase of the sensitizing capacity with increasing length of the alkyl side chain from C1 to C10, reaching a maximum at C11 and C12. On further elongation, the sensitizing potency decreased beyond C13, reaching values which finally were as low as those of the C1 and C3 derivatives. The results mirror findings which formerly have been obtained with other non-quinonoid compounds like catechols, phenols, hydroquinones and gallates. In the plant kingdom, compounds approximating an "ideal allergen" consisting of a quinonoid ring with a 10 or 11 carbon-membered side chain have been identified only once: 2,3-dimethoxy-geranyl-1,4-benzoquinone, a remarkably strong sensitizer found in Wigandia caracasana (Hydrophyllaceae).

Composition of Volatile Oil of Primula Obconica in Central China

“…In a number of sensitization experiments 2-methoxy-6-alkyl-1,4-benxoquinones with branch side chain length C1-C15, including primin, have showed an increase of the sensitizing capacity with increasing length of the alkyl side chain from C-1 to C-13 (reaching maximum activity at an alkyl chain of 10 to 11 carbons), but the sensitizing potency decreased beyond 13 carbons and the sensitization hardly occurred at C-1 to C-3. Similar results were also obtained from studies on non-quinonoid compounds like catechols, phenols, hydroquinones, and gallates (Roberts et al, 1991;Konig et al, 1993;Hausen et al, 1995). In this study, all major compounds with branch side chains identified from the wild P. obconica in China were shown to be 1 or 2 carbons in length.…”

Antituberculotic and Antiprotozoal Activities of Primin, a Natural Benzoquinone: In vitro and in vivo Studies.

“…This compound is not restricted to Primula sp., and has also been isolated from several other plants, e.g., Miconia (Melastomaceae) [6 -8] and Iris (Iridaceae) species [9]. The sensitizing effect of primin and other p-benzoquinones has been ascribed to the covalent binding of a receptor protein of epidermal cells to C(3) and C(5) of the quinone ring system, which could be attacked by nucleophiles of the receptor protein [10] [11]. We previously undertook several binding experiments with primin and 2-phenylethylamine and amino acids to investigate the mechanistic outcome of this addition reaction [12].…”

New Syntheses of the Benzoquinone Primin and its Water-Soluble Analog Primin Acid via Heck Reactions

“…The synthesis of primin (1) was first reported by Schildknecht et al in 1967 1 and later by de Lima et al 5 Primin (1) and some of its homologous alkyl analogs were subsequently prepared for structure-biological activity relationships. [14][15][16] Key steps in recent syntheses (Scheme 1) involved the addition of an alkyl Grignard to 2-hydroxy-3-methoxybenzaldehyde (3) to form the benzyl alcohol 4, 5,14 and ortho-lithiation of tetrahydropyranyl guaiacol (5) yielding 6 (ca. 60% overall yield to 1).…”