A simple and highly efficient synthetic approach to enantiopure 2-alkyl substituted tetrahydroquinoline 1 skeleton from aldehydes as starting materials and its application to the total synthesis of (+)-angustureine 2 is described.
The few frontline
antileishmanial drugs are poorly effective and toxic. To search for
new drugs for this neglected tropical disease, we tested the activity
of compounds in the Medicines for Malaria Venture (MMV) “Pathogen
Box” against Leishmania amazonensis axenic
amastigotes. Screening yielded six discovery antileishmanial compounds
with EC50 values from 50 to 480 nM. Concentration–response
assays demonstrated that the best hit, MMV676477, had mid-nanomolar
cytocidal potency against intracellular Leishmania amastigotes, Trypanosoma brucei, and Plasmodium
falciparum, suggesting broad antiparasitic activity. We explored
structure–activity relationships (SAR) within a small group
of MMV676477 analogs and observed a wide potency range (20–5000
nM) against axenic Leishmania amastigotes. Compared
to MMV676477, our most potent analog, SW41, had ∼5-fold improved
antileishmanial potency. Multiple lines of evidence suggest that MMV676477
selectively disrupts Leishmania tubulin dynamics.
Morphological studies indicated that MMV676477 and analogs affected L. amazonensis during cell division. Differential centrifugation
showed that MMV676477 promoted partitioning of cellular tubulin toward
the polymeric form in parasites. Turbidity assays with purified Leishmania and porcine tubulin demonstrated that MMV676477
promoted leishmanial tubulin polymerization in a concentration-dependent
manner. Analogs’ antiparasitic activity correlated with their
ability to facilitate purified Leishmania tubulin
polymerization. Chemical cross-linking demonstrated binding of the
MMV676477 scaffold to purified Leishmania tubulin,
and competition studies established a correlation between binding
and antileishmanial activity. Our studies demonstrate that MMV676477
is a potent antiparasitic compound that preferentially promotes Leishmania microtubule polymerization. Due to its selectivity
for and broad-spectrum activity against multiple parasites, this scaffold
shows promise for antiparasitic drug development.
in recognition of his seminal contributionst os omany aspects of organicchemistry.Abstract: An efficient total synthesis of (+ +)-petromyroxol, am arine naturalp roduct, is described. The synthesisu tilizes the Sharpless asymmetric dihydroxylation (AD), intramolecular S N 2c yclization and stereoselective Grignard reaction as key steps.The 2,5-disubstituted-3-oxygenated THF motif is found abundantly in biologically active natural products. [1] Petromyroxol (1), iso-petromyroxol (2), [2] trans-(À)-kumausyne( 3), trans-(+ +)-deacetylkumausyne (4), [3] and anthelmintic oxylipid( 5), [4] marine natural products, are few examples of dihydroxytetrahydrofurans from the acetogenin family [5] (Figure 1).The dihydroxylated THF enantiomers( + +)-petromyroxol [2a] and iso-petromyroxol [2b] were recently isolated by Li and coworkers from water conditioned with larvae of the sea lamprey, Petromyzon marinus L.,w hich is the first example of dihydroxylated THF-containingm etabolites isolated from av ertebrate. [2]
A short and highly efficient enantioselective synthetic approach to (+)-serinolamide A 1 from racemic butadiene monoepoxide as a starting material is described.
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