Synthesis and LTB4 receptor antagonist activities of the naturally occurring LTB4 receptor antagonist leucettamine A and related analogs

Abstract

The isolation and structure determination of the naturally occurring LTB4 receptor antagonist Leucettamine A (1) was recently reported. Herein we describe the synthesis of this natural product, the preparation of several analogues, and their effectiveness as antagonists of [3H]LTB4 binding to intact human U-937 cells. Total synthesis of Leucettamine A (1) is achieved by a convergent route which takes advantage of the elements of symmetry within the molecule. Syntheses of analogues of 1, which lacked the same degree of symmetry, are achieved by a different approach starting from alpha-amino acids. The natural product 1 inhibits [3H]LTB4 binding to its receptors on intact human U-937 cells with a Ki = 3.5 +/- 0.8 microM and is devoid of measurable agonist activity at the concentrations tested. 2-Amino imidazole analogues of 1 lacking the dioxolane groups were prepared. Generally these are significantly less potent than 1. However, one (26), designed on the basis of a putative structural overlay with LTB4, demonstrated potency comparable to that of the natural product (Ki = 2.4 +/- 0.2 microM).

A unified synthetic approach to the pyrazinone dragmacidins

“…In the final step of the synthesis, the penultimate aminoketone (45) was subjected to cyanamide and aqueous NaOH to produce enantiopure dragmacidin F (7). 47 Our efficient and enantiospecific route allows access to 7 in 7.8% overall yield in just 21 steps from (2)-quinic acid (28). 48 As mentioned earlier, the absolute stereochemistry of natural dragmacidin F was not known when we began our total synthesis.…”

Chemistry of 2‐Aminoimidazoles

“…Boehm et al prepared 1,4,5‐trisubstituted‐2‐aminoimidazoles by opening the symmetrical disubstituted epoxides 60 with the primary amines 61 (49–84% yield within 38 h) and oxidation of the resulting amino alcohols 62 to the amino ketone 63 with pyridinium dichromate (50–56% yield). Cyclization with cyanamide ( 2 ) led to 1,4,5‐trisubstituted‐2‐aminoimidazoles 64 (76–89% yield) by using previously employed protocol (Scheme ) .…”

Microwave-Assisted Natural Product Chemistry

“…4). Among the interesting marine sponge-derived alkaloids comprising the guanidine moiety can Dispacamide, exhibiting potent antihistamine activity and Leucettamine B, which acts as a mediator of inflammation, be mentioned [131,132]. Even though there are a number of known methods for the synthesis of the basic skeleton, there are almost no literature precedents dealing with the construction of the 2-alkylamino derivatives of the 2-aminoimidazolones.…”