The synthesis of emetine and related compounds. Part X. The synthesis of emetine analogues, including C(3)-bisnoremetine and C(3)-noremetine. Correlation of structure with amoebicidal activity

Abstract

The (&)-ketone (la) (1,3,4,6,7,11 b-hexahydro-9,l O-dimethoxybenzo[a]quinolizin-2-one) has been converted into racemic C(3)-bisnoremetine (IXa) via an N-(3,4-dimethoxyphenethyl) amide which was shown to have the same relative configuration as emetine a t C -l l b and C-2. The (-)-ketone (Ib) [3-methyl derivative of (la)],obtained by asymmetric transformation of the racemic compound, was converted into (-) -C(3)-noremetine (IXb). (-)-1',8a'-Secoemetine (XI) and the (-)-analogues (Xlla-d) have also been prepared. Only compounds (IXa), (IXb), and (XI) showed appreciable amoebicidal activity.

In VitroAmoebicidal Testing of Natural Products; Part 2. Alkaloids Related to Emetine

“…2 and 3). These findings confirm the previously studies which have demonstrated that emetine was the most potent amoebicidal agent when compared to its analogues and that changes in structure result in loss of activity (18)(19)(20)(21).…”

“…Three of the structural requirements which are necessary for the activity of emetine (1) are that the C-llb proton has the aconfiguration, the C-i' proton has the a-configuration, and that at the C-2' position there is a secondary nitrogen (7,20). Cross resistance studies using strains of Chinese hamster ovary cells have demonstrated that the phenanthrene alkaloids cryptopleurine (19) and tylocrebine (20) act in virtually an identical manner to emetine at a molecular level (10,17,25). There has been speculation that the two methoxylated aromatic rings of 19 form a planar electronegative area with the nitrogen lone pair 21 which is able to bind to a suitable ribosomal receptor.…”

“…By analogy, the same argument has been applied to emetine which is somewhat less active and can nearly achieve a planar structure 22 (17,26). Isoemetine (1), C-i' Ha-configuration) which is much less active than emetine as an amoebicide (20) cannot form the planar two electron-rich aromatic rings-secondary nitrogen triangle. The decreased activity of 9,10-dcmethoxyemetine (3), 52 and 270 times less active than emetine in the amoebicidal and cytotoxic tests respectively, (Tabs.…”

Increased Lifespan of Leukemic Mice Treated with Drugs Related to (–)-Emetine

“…In addition to the structural requirements for biological potency for mulated by Grollman [15], other considerations involving substitution at the C-3 position in the molecule come into play [6,35]. The (±)-2,3-dehydroemetine derivatives listed in table VIII lacking the appropriate ethyl group at the C-3 position do not have any antileukemic activity and are as inert as (-)-isoemetine in this respect.…”