Hirsutine alkaloids

In the same way as the hirsutine alkaloids, these alkaloids have only been isolated five times and all of them from Cocculus hirsutus. The five alkaloids were called cohirsine, cohirsitine, cohirsinine, cohirsitinine and shaheenine. The first to be isolated was cohirsine in 1987 (52-53). 

The most likely explanation for these results is that simple phenolics inhibit a very large array of enzymes in vitro. The most likely explanation for the CNS effects of Uncaria rynchophylla would be that indole alkaloids, such as dihydrocorynanteine or hirsutine (32), interact with the central neurotransmission and possibly the serotonin ergic system. 

Hirsutine (2-795), which belongs to the corynanthe subgroup of the indole alkaloids, was isolated from the plant Uncaria rhynchophylla MIQ and used for the preparation of the old Chinese folk medicine Kampo [397]. It is of pharmacological interest as it shows a strong inhibitory effect on the influenza A virus (subtype H3N2) with an EC50 = 0.40-0.57 pg ml. which is about 11- to 20-fold higher than that of the clinically used ribavirin [398]. 

A simple method was developed for the cleavage of the C-2—C-3 bond of indole alkaloids by the use of formic acid-formamide as reagent. Thus 2,3-seco derivatives of yohimbine (74), hirsutine (58), and reserpine (109) were prepared... 

During the synthesis of C-mavacurine-type alkaloids, Sakai and Shinma.reported the transformation of hirsutine to 19,203-dihydro-16-epipleiocarpamine... 

Hirsutine (85) is a corynantheine-type indole alkaloid with a C/D cis ring juncture (pseudo stereochemistry). This compound has recently been found to exhibit highly potent inhibition of the replication of the strains of influenza A (subtype H3N2) [63]. The EC50 of hirsutine was 11- to 20-fold more potent than that of the clinically used ribavirin. Exploration of the important structural features of this molecule revealed that the stereochemistry at C-3 (.R) and C-20 (R) as well as the presence of the Nb lone pair were essential for the anti-influenza A activity. Thus, the C-3 epimer, dihydrocorynantheine (86) (normal stereochemistry), was much less active than hirsutine (85). 

Recently, both hirsutine (85) and dihydrocorynantheine (86) were found to be active when the effects of these compounds on the action potentials of sino-atrial node, atrium and ventricle tissues were studied with standard microelectrode techniques [65]. In sino-atrial node preparations, both compounds concentration-dependently increased cycle length, decreased the slope of the pacemaker depolarization, decreased the maximum rate of rise and prolonged action potential duration. Thus, it was for the first time shown that hirsutine and dihydrocorynantheine have direct inhibitory effects on the cardiac pacemaker. In atrial and ventricular preparations, both compounds concentration-dependently decreased the maximum rate of rise and prolonged action potential duration. Although stereochemically different, these two alkaloids exhibited no difference in their effects on various myocardial action potential parameters. Dihydrocorynantheine also displays potent a-adrenoceptor blocking activity, while hirsutine is inactive [66]. Experiments with ion channels indicate that the mechanisms for these two phenomena probably differ. The direct effects of hirsutine and dihydrocorynantheine on the action potential of cardiac muscle through inhibition of multiple ion channels may explain the negative chronotropic and antiarrhythmic activities of these two alkaloids. 

The three-component domino-Knoevenagel-hetero-Diels-Alder reaction is especially fruitful if one uses aldehydes containing a protected amino function. In such cases the formed dihydropyranyl ether moiety can be used as a source of an aldehyde moiety that can undergo a condensation with the amino group after deprotection. Thus, several alkaloids such as hirsutine 108, dihydrocorynantheine... 

The alkaloids hirsutine (1) and its 3or-epimer dihydrocorynantheine (2a) belong to the corynanthe group of indole alkaloids. They have been isolated from the plant Uncaria rhynchophylla MIQ, which was used for the preparation of the old Chinese folk medicine kampo . Nowadays, 1 and related compounds attract great attention in medicine because of their growth inhibition of the influenza A subtype H3N2 virus. With an EC50 value of 0.40-0.57 ig/mL 1 has shown itself to be 10-20 times more active than the clinically used drug ribavirine (3).1,2 Furthermore, 1 is known for its antihypertensive and antiarrhythmic activity.3... 

The indole alkaloids of Mitragyna hirsuta Havil, M.javanica Koord. et Val. var. microphylla Craib, M. speciosa, and Nauclea coadunata are mostly in the corynantheine-heteroyohimbine-yohimbine group. The alkaloids isolated from the leaves of Mitragyna hirsuta have been identified as hirsutine, rhynchophylline, isorhynchophylline, mitraphylline, isomi-... 

The same phenomenon was observed for mitraciliatine (10) and the closed ring E alkaloids 14-19, where the percentage metabolism by O-demethylation estimated by formaldehyde production ( 1%) was much less than the degree of total metabolism (25-69%). Nevertheless, both hirsutine and mitraciliatine gave detectable amounts of a compound assumed by TLC analysis to be an 0-(17)-demethyl metabolite, whereas such was not the case with 14-19. Hirsutine and mitraciliatine were also metabolized (to unidentified products) by both rat and guinea pig liver microsomes, which did not metabolize alkaloids 4-6, 9, and 11-13. 

The domino Knoevenagel condensation hetero-Diels-Alder reaction was used for the enantioselective total synthesis of the active anti-influenza A virus indole alkaloid hirsutine and related compounds by L.F. Tietze and co-workers. The Knoevenagel condensation was carried out between an enantiopure aldehyde and Meldrum s acid in the presence of ethyienediamine diacetate. The resulting highly reactive 1-oxa-1,3-butadiene underwent a hetero-Diels-Alder reaction with 4-methoxybenzyi butenyl ether ElZ = 1 1) in situ. The product exhibited a 1,3-asymmetric induction greater than 20 1. 

LTA oxidation-mediated epimerization of indole alkaloids has also been performed. Brown et al. (83) synthesized (-l-)-dihydroisositsirikine (258) and (+)-dihydrocorynantheine (259) by epimerization at C-3 on LTA oxidation followed by sodium borohydride reduction of the (-)-)-compound 256 and ( + )-hirsutine (257) (Scheme 30). 

Ca2+ channels are inhibited by several bis-isoquinoline alkaloids (e.g., berbamine, hernandezine, liensinine, monterine, tetrandine), aporphines (e.g., glaucine, norushinsunine), complex indole alkaloids (bis-nortoxiferine, hirsutine, mitragynine, paspaline, paspalitrem, paxilline, penitrem), or other bulky alkaloids (agelasine, contotoxins, crambescidin, ryanodine). Many channel blocker occur in animal venoms it has been estimated that 10% of marine natural products have these properties [65]. 

In connection with partial synthesis in the ring-E-seco alkaloids and the heteroyohimbine group, several Nb-oxides have been prepared. Dihydrocory-nantheine, on oxidation with m-chloroperbenzoic acid, affords two epimeric Nb-oxides whereas its pseudo isomer, hirsutine, gives only one. Desmethyl-hirsuteine Nb-oxide (91), when treated with trifluoroacetic anhydride in methylene chloride, undergoes the Polonovski reaction reduction of the product by means of buffered sodium cyanoborohydride then affords a mixture of desmethylcorynantheine (92), 3-i5o-rauniticine (93), and akuammigine (94) (Scheme 12). Clearly, formation of an immonium ion can occur in the Polonovski reaction either towards C-3 [- (95)], which results in the ultimate epimeriza-... 

Oxindole and indole alkaloids corynoxeine, hirsutine, and hirsuteine from uncaria Uncaria rhynchophylla Miq.) as the main compounds of the extract destabilize the formation of Ap aggregates [185]. They also have a neuropro-tective effect and inhibit glutamate-induced neurotoxicity in the cells of the cerebellum [186]. 

In conclusion of this part of synthesis, usefulness of enamide prepared from harmalane with 3-furoyl chloride was firmly demonstated by its application to the synthesis of relatively untouched alkaloids of corynantheine group of alkaloids. Actually, we have succeeded in the synthesis of geissoschizine and hirsu-teine, thereby extended to the formal synthesis of corynantheine and hirsutine. Further, unexploited alkaloids rhazimanine and isositsirikine were also synthesized, thereby shed light on the chemistry of these groups of alkaloids. Full clarification of the problems on their structures will be achieved. 

Scheme 3. Tietze s biomimetic synthesis of the alkaloid hirsutine (20) through a domino Knoevenagel/ hetero-Diels-Alder sequence.

Yano S, Horiuchi H, Horie S, Aimi N, Sakai S, Watanabe K (1991) Ca channel blocking effects of Hirsutine, an indole alkaloid from Uncaria genus, in the isolated rat aorta. Planta Med 57 403 05. doi 10.1055/s-2006-960134... 

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