Controlled masking and targeted release of redox-cycling ortho-quinones via a C-C bond-cleaving 1,6-elimination.

Natural products that contain ortho-quinones show great potential as anticancer agents but have been largely discarded from clinical development because their redox-cycling behaviour results in general systemic toxicity. Here we report conjugation of ortho-quinones to a carrier, which simultaneously masks their underlying redox activity. C-benzylation at a quinone carbonyl forms a redox-inactive benzyl ketol.

Site-selective protein-modification chemistry for basic biology and drug development.

Nature has produced intricate machinery to covalently diversify the structure of proteins after their synthesis in the ribosome. In an attempt to mimic nature, chemists have developed a large set of reactions that enable post-expression modification of proteins at pre-determined sites. These reactions are now used to selectively install particular modifications on proteins for many biological and therapeutic applications.

Dual-stage triterpenoids from an African medicinal plant targeting the malaria parasite.

Sixteen triterpenoids (1-16), previously isolated from the aerial parts of the African medicinal plant Momordica balsamina or obtained by derivatization, were evaluated for their activity against liver stages of Plasmodium berghei, measuring the luminescence intensity in Huh-7 cells infected with a firefly luciferase-expressing P. berghei line, PbGFP-Luccon. Toxicity of compounds (1-16) was assessed on the same cell line through the fluorescence measurement of cell confluency.

Flavones as isosteres of 4(1H)-quinolones: discovery of ligand efficient and dual stage antimalarial lead compounds.

Malaria is responsible for nearly one million deaths annually, and the increasing prevalence of multi-resistant strains of Plasmodium falciparum poses a great challenge to controlling the disease. A diverse set of flavones, isosteric to 4(1H)-quinolones, were prepared and profiled for their antiplasmodial activity against the blood stage of P. falciparum W2 strain, and the liver stage of the rodent parasite Plasmodium berghei.

Quinolin-4(1H)-imines are potent antiplasmodial drugs targeting the liver stage of malaria.

We present a novel series of quinolin-4(1H)-imines as dual-stage antiplasmodials, several-fold more active than primaquine in vitro against Plasmodium berghei liver stage. Among those, compounds 5g and 5k presented low nanomolar IC50 values. The compounds are metabolically stable and modulate several drug targets.

Drug screen targeted at Plasmodium liver stages identifies a potent multistage antimalarial drug.

Plasmodium parasites undergo a clinically silent and obligatory developmental phase in the host's liver cells before they are able to infect erythrocytes and cause malaria symptoms. To overcome the scarcity of compounds targeting the liver stage of malaria, we screened a library of 1037 existing drugs for their ability to inhibit Plasmodium hepatic development. Decoquinate emerged as the strongest inhibitor of Plasmodium liver stages, both in vitro and in vivo.

Novel potent metallocenes against liver stage malaria.

Novel conjugates of the antimalarial drug primaquine (compound 1) with ferrocene, named primacenes, have been synthesized and screened for their activities against blood stage and liver stage malaria in vitro and host-vector transmission in vivo. Both transmission-blocking and blood-schizontocidal activities of the parent drug were conserved only in primacenes bearing a basic aliphatic amine group. Liver stage activity did not require this structural feature, and all metallocenes tested were comparable to or better than primaquine in this regard.

Triterpenoids as inhibitors of erythrocytic and liver stages of Plasmodium infections.

Bioassay-guided fractionation of the methanol extract of Momordica balsamina led to the isolation of two new cucurbitane-type triterpenoids, balsaminol F (1) and balsaminoside B (2), along with the known glycosylated cucurbitacins, cucurbita-5,24-diene-3β,23(R)-diol-7-O-β-D-glucopyranoside (3) and kuguaglycoside A (4). Compound 1 was acylated yielding two new triesters, triacetylbalsaminol F (5) and tribenzoylbalsaminol F (6). The structures were elucidated based on spectroscopic methods including 2D-NMR experiments (COSY, HMQC, HMBC and NOESY).

4-C-Me-DAB and 4-C-Me-LAB - enantiomeric alkyl-branched pyrrolidine iminosugars - are specific and potent α-glucosidase inhibitors; acetone as the sole protecting group.

The syntheses of 4-C-Me-DAB [1,4-dideoxy-1,4-imino-4-C-methyl-d-arabinitol] from l-erythronolactone and of 4-C-Me-LAB [from d-erythronolactone] require only a single acetonide protecting group. The effect of pH on the NMR spectra of 4-C-Me-DAB [pK(a) of the salt around 8.4] is discussed and illustrates the need for care in analysis of both coupling constants and chemical shift.

3-O-Benzhydryl-2,5-dide-oxy-2,5-imino-2-C-methyl-l-lyxono-1,4-lactone.

The title bicyclic lactone, C(19)H(19)NO(3), is an inter-mediate in the synthesis of chiral α-methyl-prolines and branched C-methyl pyrrolidines; the absolute configuration was determined by the use of d-erythronolactone as the starting material. It exhibits no unusual crystal packing features, and each mol-ecule acts as a donor and acceptor for one C-H⋯O hydrogen bond.