Bisindole natural products consist of two monomeric indole alkaloid units as their obligate constituents. Bisindoles are more potent with respect to their biological activity than their corresponding monomeric units. In addition, the synthesis of bisindoles are far more challenging than the synthesis of monomeric indole alkaloids. Herein is reviewed the enantiospecific total and partial synthesis of bisindole alkaloids isolated primarily from the Alstonia genus of the Apocynaceae family. The monomeric units belong to the sarpagine, ajmaline, macroline, vobasine, and pleiocarpamine series. An up-to-date discussion of their isolation, characterization, biological activity as well as approaches to their partial and total synthesis by means of both synthetic and biosynthetic strategies are presented.
An enolate driven copper-mediated cross-coupling process enabled a cheaper and greener access toward the key pentacyclic intermediates required for the enantiospecific total synthesis of a number of C-19 methyl substituted sarpagine/macroline indole alkaloids. Replacement of palladium (60–68%) with copper iodide (82–89%) resulted in much higher yields. The formation of an unusual 7-membered cross-coupling product was completely inhibited by using TEMPO as a radical scavenger. Further functionalization led to the first enantiospecific total synthesis of macrocarpine D and E.
Extension of the asymmetric Pictet-Spengler reaction to bulkier N -alkylated tryptophan derivatives resulted in an improved stereospecific access to the key bicyclo[3.3.1]nonane core of bioactive C-19 methyl substituted sarpagine/macroline/ajmaline indole alkaloids with excellent diastereoselectivity by internal asymmetric induction. Complete stereocontrol of the C-19 methyl function in either the α- or β-configuration was achieved, which enables the total synthesis of any member from this group of thirty alkaloids. We report herein, the total synthesis of macrocarpines (A-C) 1-3, talcarpine 4, N(4)-methyl-N(4),21-secotalpinine 5, dihydroperaksine 8 and deoxyperaksine 9.
Increasing
evidence implicates the orphan G protein-coupled receptor
88 (GPR88) in a number of striatal-associated disorders. In this study,
we report the design and synthesis of a series of novel (4-alkoxyphenyl)glycinamides
(e.g., 31) and the corresponding 1,3,4-oxadiazole bioisosteres
derived from the 2-AMPP scaffold (1) as GPR88 agonists.
The 5-amino-1,3,4-oxadiazole derivatives (84, 88–90) had significantly improved potency and lower lipophilicity compared
to 2-AMPP. Compound 84 had an EC50 of 59 nM
in the GPR88 overexpressing cell-based cAMP assay. In addition, 84 had an EC50 of 942 nM in the [35S]GTPγS
binding assay using mouse striatal membranes but was inactive in membranes
from GPR88 knockout mice, even at a concentration of 100 μM.
In vivo pharmacokinetic testing of 90 in rats revealed
that the 5-amino-1,3,4-oxadiazole analogues may have limited brain
permeability. Taken together, these results provide the basis for
further optimization to develop a suitable agonist to probe GPR88
functions in the brain.
The orphan receptor GPR88 has been implicated in a number of striatal-associated disorders, yet its endogenous ligand has not been discovered. We have previously reported that the amine functionality in the 2-AMPP-derived GPR88 agonists can be replaced with an amide (e.g., 4) without losing activity. Later, we have found that the amide can be replaced with a bioisosteric 1,3,4-oxadiazole with improved potency. Here, we report a further study of amide bioisosteric replacement with a variety of azoles containing three heteroatoms, followed by a focused structure-activity relationship study, leading to the discovery of a series of novel 1,4-disubstituted 1H-1,2,3-triazoles as GPR88 agonists. Collectively, our medicinal chemistry efforts have resulted in a potent, efficacious, and brain-penetrant GPR88 agonist 53 (cAMP EC 50 = 14 nM), which is a suitable probe to study GPR88 functions in the brain.
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