Novel Hypotensive Agents from Verbesina caracasana. 6. Synthesis and Pharmacology of Caracasandiamide

Abstract

Caracasandiamide, a second hypotensive agent isolated from Verbesina caracasana, is the cyclobutane dimer (truxinic type) of the previously reported 1-[(3, 4-dimethoxycinnamoyl)amino]-4-[(3-methyl-2-butenyl)guanidino]butane (caracasanamide) (Delle Monache, G.; et al. BioMed. Chem. Lett. 1992, 25, 415-418). The structure was confirmed by synthesis starting from beta-truxinic acid obtained by photoaddition of 3, 4-dimethoxycinnamic acid. The dimer was coupled with 2 mol of prenylagmatine to give caracasandiamide in satisfactory yield. By contrast, the direct photodimerization of caracasanamide was unsuccessful. Caracasandiamide, assayed by the iv route in anesthetized rats at doses ranging from 50 to 3200 microgram/kg of body weight, was found to have no appreciable effect on heart rate. At lower doses, the drug stimulates breathing and increases cardiac inotropism, stroke volume, and cardiac output, thus augmenting blood pressure and aortic flow. At higher doses, caracasandiamide depresses breathing likely through central neurogenic mechanisms (not involved in the cardiovascular effects), continues to stimulate cardiac inotropism, and induces, by reducing peripheral vascular resistance, arterial hypotension with reduction of both aortic flow and stroke volume. These cardiovascular effects appear to involve complex interactions at the level of the peripheral beta(1)-, beta(2)-, and alpha(2)-adrenoreceptor-dependent as well as M(2)- and M(4)-cholinergic receptor-dependent transductional pathways both in cardiovascular myocells and at the level of the postganglionic sympathetic endings (with reserpine- and guanethidine-like mechanisms). The cardiovascular effects of caracasandiamide, different from those of caracasanamide, do not depend on significant actions on the central nervous system and on baroreflex pathways. In a similar manner and more effective than caracasanamide, caracasandiamide may be considered a hypotensive and antihypertensive drug. It is devoid of some of the negative side effects, e.g., reflex tachycardia and decreased cardiac inotropism, which are shown by the majority of the most common antihypertensive and vasodilator drugs.

Cage-confined photocatalysis for wide-scope unusually selective [2 + 2] cycloaddition through visible-light triplet sensitization

“…2b ). β -truxinic ester derivatives, presenting as an important family of natural products 1 – 3 , can be generated facilely in moderate to high yields ( 30 – 61 ). Generally, para -functionalized cinnamates result in excellent d.r.…”

“…It is noteworthy that β -truxinic esters bearing hydroxyl or methoxy group ( 33 , 60 and 61 ) are obtained exclusively as the syn -HH diastereomers. Among them, the dimethoxy β -truxinic ester 60 was previously produced in 25% 2 and 40% 3 yields by solid-state photodimerization as the crucial intermediate for caracasandiamide synthesis. Moreover, satisfactory results are achieved when applying para -substituted benzylideneacetones as substrates (Fig.…”

“…Cyclobutane scaffolds are prevalent in natural products and bioactive compounds 1 – 3 , therefore triggering tremendous synthetic interests in constructing four-membered carbocycles 4 , 5 . Since the first report in 1877 6 , UV light-induced [2 + 2] cycloaddition of alkenes has been conveniently used to generate cyclobutane backbones 7 .…”

“…Nevertheless, owing to steric preference and relative radical stability of excited-state intermediates, hitherto, the stereochemical control is mainly achieved for the thermodynamic favored anti-diastereomers from acyclic olefins, e.g., styrenes, chalcones, and cinnamates 16 , 21 – 24 . A general synthetic strategy for thermodynamic unfavored syn -diastereomers, which present as the important backbones of many biological active natural products 1 – 3 , remains underdeveloped and desired for a long time 25 , 26 .…”

Marine Terpenoid Diacylguanidines: Structure, Synthesis, and Biological Evaluation of Naturally Occurring Actinofide and Synthetic Analogues

“…Despite their low occurrence, guanidine terpenoids have shown a large spectrum of biological activities, standing out as promising lead structures suitable for development of potential drugs . As an example, recent studies have indicated the ability of some of these compounds (e.g., nitensidine A) to modulate the activity of human P-glycoprotein ABCB1, a transmembrane efflux pump belonging to the ATP-binding cassette (ABC) transporter superfamily, which is involved in cancer multidrug resistance …”