Kristina Luthman

Caco-2 monolayers in experimental and theoretical predictions of drug transport

This review examines the use of Caco-2 monolayers in the prediction of intestinal drug absorption. First, the different routes of drug transport in Caco-2 monolayers are compared with those seen in vivo. Second, the prediction of drug absorption in vivo from transport experiments in cell monolayers is discussed for different classes of drugs. Finally, the use of Caco-2 monolayers as a reference model in physico-chemical and theoretical predictions of drug absorption is discussed. We conclude that Caco-2 monolayers can be used to identify drugs with potential absorption problems, and possibly also to select drugs with optimal passive absorption characteristics from series of pharmacologically active molecules generated in drug discovery programs.

Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in Humans

AbstractPurpose. A theoretical method has been devised for prediction of drug absorption after oral administration to humans. Methods. Twenty structurally diverse model drugs, ranging from 0.3 to 100% absorbed, were investigated. The compounds also displayed diversity in physicochemical properties such as lipophilicity, hydrogen bonding potential and molecular size. The dynamic molecular surface properties of the compounds were calculated, taking into account their three-dimensional shape and flexibility. Results. An excellent sigmoidal relationship was established between the absorbed fraction after oral administration to humans (FA) and the dynamic polar molecular surface area (PSAd) (r2 = 0.94). The relationship was stronger than those obtained for more established predictors of drug absorption. Drugs that are completely absorbed (FA > 90%) had a PSAd ≤ 60 Å2 while drugs that are < 10% absorbed had a PSAd > 140 Å2. Conclusions. The results indicate that PS Ad can be used to differentiate poorly absorbed drugs at an early stage of the drug discovery process.

On the Use of C2-Symmetric Aziridines as Chiral Auxiliaries

Abstract A systematic study has been made of the utility of readily available C 2 -symmetric aziridines as auxiliaries for asymmetric alkylation and aldol rea

A 2-deoxy analogue of KDO as the first inhibitor of the enzyme CMP-KDO synthetase.

The two KDO analogues 2,6-anhydro-3-deoxy-D-glycero-D-galacto-octonate and 2,6-anhydro-3-deoxy-D-glycero-D-talo-octonate were synthesized and tested as inhibitors of the enzyme CTP:CMP-deoxyoctulosonate cytidylyltransferase (CMP-KDO synthetase) from Gram-negative bacteria. Only compound 4, the 2-deoxy analogue of beta-KDO-pyranose, was found to be an inhibitor with a Ki of 3.9 microM.

Novel L-Phe-Gly mimetics

Abstract The syntheses of some novel dipeptidomimetics of potential biological interest are described. The reactions started from the vinyl isostere of Phe-Gly and were performed in high yields. Stereochemically pure products were isolated.

Mechanism of the antigen formation of carvone and related alpha, beta-unsaturated ketones

In the present study, the mechanism for the antigen formation of α, β‐unsaturated ketones was investigated. A series of analogues of carvone ((5R)‐5‐isopropenyl‐2‐methyl‐2‐cyclohexenone) with altered chemical reactivity and with retained overall structure or with retained reactivity and altered three‐dimensional structure were synthesized. These analogues were tested for cross‐reactivity in carvone‐sensitized animals. Cross‐reactivity was observed for analogue 3 ((5R)‐5‐isopropyl‐2‐methyl‐2‐cyclohexen‐1‐one). No cross‐reactions were observed for analogues 1 ((2R,5R)‐5‐isopropenyl‐2‐methyl cyclohexanone) and 4 ((5R)‐2,3‐dimethyl‐5‐isopropenyl‐2‐cyclohexene‐1‐one). Both those compounds also failed to induce sensitization. These findings demonstrate that α, β‐unsaturated ketones form antigens after a nucleophilic attack at the β‐carbon with soft nucleophiles such as thiol in cysteine and not with the formation of a Schiff’s base after a nucleophilic attack at the carbonyl carbon with nitrogen nucleophiles. Furthermore, no cross‐reactivity was observed between R‐ and S‐carvone indicating the importance of the 3‐dimensional structure of haptens (and antigens) in T‐cell recognition. The analogues were also tested for cross‐reactivity on patients allergic to carvone. The results from the animal study were confirmed.

1,2,4-Oxadiazole derivatives of phenylalanine: potential inhibitors of substance P endopeptidase

Abstract The synthesis and the biological activity of a series of benzyl or aryl substituted 1,2,4-oxadiazole derivatives of phenylalanine are described. A base-promoted intermolecular cyclization reaction was performed using racemic tert -butyloxycarbonyl-protected phenylalanine methyl ester and an amidoxime. After deprotection of the amino function the compounds were evaluated for their affinity to rat brain NK 1 -receptors and as inhibitors of a specific substance P cleaving enzyme, substance P endopeptidase (SPE), isolated from human cerebrospinal fluid. The results indicate that several compounds are weak inhibitors of SPE. However, all compounds lacked appreciable NK 1 -receptor affinity.

Synthesis of C-(β-D-glycosyl) analogues of 3-deoxy-D-manno-2-octulosonic acid (Kdo) as potential inhibitors of CMP(Kdo synthetase

Eight C-(beta-D-glycosyl) analogues (14-21) of Kdo (3-deoxy-D-manno-2-octulosonic acid) were obtained from isopropylidene-protected ester precursors and tested in vitro for their inhibitory activity on CMP-Kdo synthetase. None had more than minor inhibitory activity.

DIASTEREOSELECTIVE PERACID EPOXIDATION : CONTROL OF THE FACE SELECTIVITY VIA FUNCTIONAL GROUP TUNING AND PROPER CHOICE OF EPOXIDATION REAGENT

Abstract Peracid epoxidation of 1a-f with 3-chloroperbenzoic acid ( m -CPBA) and trifluoroperacetic acid (CF 3 CO 3 H) show different stereoselectivities. The olefins are substituted with two directing groups which are expected to direct the peracid to opposite faces of the alkene. Optimal face selectivities could be achieved by the proper choice of directing groups and epoxidation reagent.

Synthesis of analogues of 3-deoxy-D-manno-octulosonic acid (KDO) as potential inhibitors of CMP-KDO synthetase

A series of derivatives of the 2-deoxy analogue of beta-KDO (2,6-anhydro-3-deoxy-D-glycero-D-talo-octonic acid; ammonium salt, 2) has been synthesised as potential inhibitors of CMP-KDO synthetase, starting from methyl 2,6-anhydro-3-deoxy-4,5:7,8-di-O-isopropylidene-D-glycero-D-talo- octonate and replacing the CO2Me group attached to C-2 variously by CONH2, CONHOH, CH2OH, CH2PO(OH)(O-NH4+), COCH2PO(OH)(O-H3N+pheny), CH2CO2-NH4+, CON-HCH2CO2-NH4+, CONHBn, CONHHexyl, CO2Bn, and CO2Hexyl. Of these derivatives, the hydroxamic acid (CONHOH) was the best inhibitor of CMP-KDO synthetase, but was less potent than 2.