Christian Miculka

Abstract: In this article, we present the synthesis of a series of oligo(oxymethylenes) capped with 1-phenylethanol and MeOH. The anionic condition affords enantiomerically pure oligo(oxymethylene) oligomers, while the cationic oligomerization leads to a racemic mixture of the oligo(oxymethylene) chain.

Abstract: Orlistat, a satd. deriv. of naturally occurring lipstatin, is administered orally as an anti-obesity agent in humans. It acts as a covalent inhibitor of lipases, thereby blocking the hydrolysis of triglycerides from nutrition into free fatty acids. Orlistat also inhibits the C-terminal enzymic domain of fatty acid synthetase (FAS). In both cases, binding to and inhibition of the serine hydrolase domain is the presumed mode of action. As the fatty acid synthesis of protozoan parasites has been extensively discussed as a valid target for pharmaceutical intervention, an investigation was made into orlistat's effect on Plasmodium falciparum and Toxoplasma gondii in cell cultures. The in vitro replication of blood-stage P. falciparum in human erythrocytes and intracellular growth of the tachyzoite form of T. gondii was found to be inhibited at submicromolar concns. Blast searches for a serine hydrolase consensus pattern in the proteomes of P. falciparum, T. gondii and Eimeria tenella showed that a no. of proteins contain the serine hydrolase pattern. The amino acid sequences surrounding the serine active sites, including the human enzyme, displayed three conserved amino acid residues, G × S × G. While these proteins are serine hydrolases with high probability, their cellular functions are unknown. These studies provide the foundation to conduct efficacy studies on E. tenella in cell culture, and to explore orlistat's potential for the prophylaxis or treatment of coccidiosis in chicken and diseases caused by other apicomplexans. [on SciFinder(R)]

Abstract: The beta-adrenergic agonist 1 (zilpaterol) is used as production enhancer in cattle. Binding experiments of separated enantiomers on recombinant human beta(2)-adrenergic and mu-opioid receptors and functional studies showed that the (-)-1 enantiomer accounts for essentially all the beta(2)-adrenergic agonist activity and that it exhibits less affinity toward the mu-opioid receptor than (+)-1, which is a mu-opioid receptor antagonist. X-ray crystallography revealed the absolute configuration of (-)-1 to be 6R,7R.

Abstract: Praziquantel (PZQ) is the drug compound of choice in the control and treatment of schistosomiasis. PZQ is administered as a racemate, i. e. 1ratio1 mixture of enantiomers. The schistosomicidal activity arises from one PZQ-enantiomer, whereas the other enantiomer does not contribute to the activity. The WHO's Special Programme for Research and Training in Tropical Diseases (TDR) has assigned the low-cost preparation of pure schistosomicidal (-)-PZQ a key priority for future R&D on PZQ, but so far this transition has not happened. PZQ has two major administration drawbacks, the first being the high dose needed, and its well documented bitter and disgusting taste. Attempts of taste-masking by low-cost means have not been successful. We hypothesized that the non-schistosomicidal component in PZQ would be the main contributor to the unpleasant taste of the drug. If the hypothesis was confirmed, the two major administration drawbacks of PZQ, the high dose needed and its bitter taste, could be addressed in one go by removing the component contributing to the bitter taste.

Abstract: A review. Drug discovery aims at finding a previously unknown applicability of a substance as a drug. It entails the mapping of properties of substances against a set of criteria which define the applicability. It would be preferable to start from desired properties, as given by the criteria, and deduce de novo the substances which would have these properties. This would allow the design of the most suitable chem. out of the virtually infinite no. of chems. structurally conceivable. The knowledge base, however, by and large does not exist. Therefore, the starting points for drug discovery are not the desired properties, but phys. existing chems. which are then exposed to suitable model expts. in high nos. to det. their properties. We were interested in the question of whether relationships could be obtained from the calcd. properties of registered veterinary pharmaceuticals which could guide the selection of compds. for property detn. We learned that calcd. properties mainly relate to the structural origin of the active pharmaceutical ingredients, either natural or non-natural. In contrast, measured permeability and lipophilicity values allow for differentiation between classes, such as those having different application forms, but they are independent of the structural origin of the active pharmaceutical ingredients. Translation between these simple structural descriptors and property space does not seem feasible. We encourage the continued search for descriptors which allow a correlation of the structural space with the property space. Veterinary drug discovery, and pharmaceutical research in general, will greatly profit from the resoln. of this apparent dichotomy. [on SciFinder(R)]

Abstract: The title compound, C(21)H(28)O(8), crystallizes with two independent molecules, each with a crystallographic twofold axis passing through the central CH(2) group. The two molecules have different orientations of the terminal benzyl groups. The average C-O bond length in the polyoxymethylene helix, corrected for librational motion, is 1.419 A. The molecules are connected into layers by intermolecular C-H...O and C-H...pi(phenyl) interactions.

Abstract: The title compd., C19H24O6, crystallizes with two half-mols. per asym. unit; each mol. has a crystallog. 2-fold axis passing through the central CH2 group. The two mols. have different orientations of the terminal benzyl groups. The C-O bond lengths in the central section of each polyoxymethylene helix are almost const. The av. C-O bond length, cor. for librational motion, is 1.421 Å. The mols. are connected into layers by intermol. C-H···O and C-H···π(phenyl) interactions. The structure was previously reported by Noe, Miculka and Bats (1994). Crystallog. data and at. coordinates are given. [on SciFinder(R)]

Abstract: The trans-enantiomers of the commercially important anti-protozoal compound Halofuginone have been prepared and characterized, and the absolute configuration was assigned by X-ray crystallography. The activity of both enantiomers against Cryptosporidium parvum was determined in vitro and related to acute toxicity in vivo. It was shown that both the activity and the toxicity are properties of the (2R,3S)-enantiomer. We conclude that with respect to broadening the therapeutic window there is no advantage in application of one enantiomer over the application of the racemic mixture in the treatment of C. parvum infections.

Abstract: In the context of Eschenmoser's work on pyranosyl-RNA ('p-RNA'), we investigated the synthesis and base-pairing properties of the 5-methylisocytidine deriv. The previously detd. clear-cut restrictions of base-pairing modes of p-RNA had led to the expectation that a 5-methylisocytosine β-D-ribopyranosyl (= D-pr(MeisoC)) based (4'→2')-oligonucleotide would pair inter alia with D-pr(isoG) and L-pr(G) based oligonucleotides (D-pr and L-pr = pyranose form of D- and L-ribose, resp.). Remarkably, we could not observe pairing with the D-pr(isoG) oligonucleotide but only with the L-pr(G) oligonucleotide. Our interpretation concludes that this - at first hand surprising - observation is caused by a change in the nucleosidic torsion angle specific for isoC. [on SciFinder(R)]

Abstract: Pyranosyl-RNA ("p-RNA") is an oligonucleotide system isomeric to natural RNA and composed of the very same building blocks as RNA. Its generational, chem., and informational properties are deemed to be those of an alternative nucleic acid system that could have been a candidate in Nature's evolutionary choice of the mol. basis of genetic function. We consider the study of the chem. of p-RNA as etiol. relevant in the sense that knowledge of its structural, chem., and informational properties on the chem. level offers both a perspective and ref. points for the recognition of specific structural assets of the RNA structure that made it the (supposedly) superior system among possible alternatives and, therefore, the system that became part of biol. as we know it today. The paper describes the chem. synthesis of β-D- (and -L)-ribopyranosyl-(4'→2')-oligonucleotide sequences, presents a resume of their structural and chem. properties, and cautiously discusses what we may and may not have learned from the pyranosyl isomer of RNA with respect to the conundrum of RNA's origin. [on SciFinder(R)]

Abstract: Racemic ribose is synthesized in 7 steps starting from D-glucose. [on SciFinder(R)]

Abstract: The authors report here pyranosyl-RNA: base pairing between homochiral oligonucleotide strands of opposite sense of chirality. [on SciFinder(R)]

Abstract: Acid-catalyzed etherification of various alkylarylcarbinols 1 leads to a mixt. of diastereomeric products 2 and 3. As found in the closely related formation of diastereomeric acetals, the ratio 2/3 is shown to be time-dependent. Preferred formation of the meso-diastereomer 3 under kinetic conditions and preferred formation of the racemic diastereomer 2 under thermodn. conditions is obsd. A reaction path based on π-π interactions and stereoelectronic effects is presented to explain exptl. results. [on SciFinder(R)]

Abstract: An x-ray structure anal. of PhCH2O[CH2O]5CH2Ph was interpreted in terms of stereoelectronic effects. [on SciFinder(R)]

Abstract: Chiral secondary alcs. which are protected with the enantiomerically pure endo- or exo-octahydro-7,7,8-trimethyl-4,7-methanobenzofuran-2-ol show significant differences in 13C-chem. shifts around the glycosidic linkage. An easy method for detn. of the abs. configuration of secondary alcs. based on this fact is described. [on SciFinder(R)]

Abstract: X-ray anal. of meso-bis[1-(9-anthryl)ethyl] ether showed the existence of two bridged species in the unit cell besides the expected mol. The addnl. bonds between the 9- and 10-positions of the anthracene moieties were extraordinarily long. This fact leads to conclusions on the reactive behavior of arylalkyl carbinols upon acid-catalyzed etherification. [on SciFinder(R)]

Abstract: Alkylthienylcarbinols contain a thiophene ring as precursor for a C4-alkyl chain. The racemic alkylthienylcarbinols were treated with lactols to give the resp. acetals which were sepd. by crystn. or chromatog. more easily than the corresponding carbinols. Reductive desulfurization of the acetals gave the O-protected carbinols which were converted to the enantiomerically pure carbinols. E.g., reaction of (±)-α-methyl-2-thiophenemethanol with [3aS-(2α,3aα,4α,7α,7aα)]octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-ol gave the resp. lactol deriv. and sepn. of the latter by column chromatog. gave a diastereomer derived from (R)-2-hexanol and from (S)-2-hexanol in 96.2% diastereomeric excess (ee) each. Deprotection of the latter gave (R)-2-hexanol (96% ee) and (S)-2-hexanol (96% ee), resp. [on SciFinder(R)]

Abstract: Zilpaterol enantiomer compns. (esp. those in which 6R,7R-zilpaterol predominates) have application in enhancing wt. gain, improving feed efficiency, and/or increasing carcass leanness in livestock, poultry, and/or fish. Thus, 6R,7R-zilpaterol (0.2 mg/kg) in feed is used to improve wt. gain of cattle. The compns. may also be used in medicaments. Benzyl carbamate derivs. may be formed to sep. the enantiomers. A method for detg. the abs. configuration of zilpaterol enantiomers comprises x-ray crystallog. of the 4-bromophenylacyl derivs. [on SciFinder(R)]

Abstract: The invention relates to antiparasitic compns. comprising atipamezole or its pharmaceutically acceptable salt and amitraz and their use in a method to control ectoparasite infestations on animals. [on SciFinder(R)]

Abstract: R2Z2ZZ1R1 [I; R1 = alk(en)yl, (hetero)aryl, etc.; R2 = Z3NR7R8; R7,R8 = H alkyl, aryl, etc.; Z = (un)substituted thiazole-4,2-diyl; Z1 = bond or (un)substituted imino; Z2 = (un)substituted phenylene; Z3 = bond, CO, SO2] were prepd. Thus, 3-(ClO2S)C6H4COCH2Br was cyclocondensed with PhNHCSNH2 and the product amidated by PhCH2NHMe to give title compd. II. Data for biol. activity of I were given. [on SciFinder(R)]

Abstract: Title compds. [(I); Base = (un)protected (un)substituted natural or unnatural nucleic acid base group; R = H, Br, Cl, OR1; R1 = H, linking group, phosphoramidite, phosphinate; R2 = H, protecting group, or phosphate-bridged 2'→4' I, with similar or different Base], with D- or L-erythro or -threo configurations, were prepd., for use as therapeutic agents or electronic solid-phase diagnostic units (no data) or for conjugate formation with biomols. such as peptides, antibodies, or nucleic acids (no data). Thus, 1,2-O-isopropylidene-5-O-trityl-α-D-xylo-furanose is 3'-deoxygenated, 5'-detritylated, the α-furan form transformed to the 1,2,4-tri-O-benzoyl-protected-α-pyran using trifluoroacetic acid ion-exchange technique (25% yield), and reacted with a nucleic acid base to give, e.g., I (Base = thymine; R, R2 = COPh), which can be further reacted to give the 3'-deoxy-4'-O(4,4'-dimethoxytrityl)-2'-O-(2-cyanoethyl-N,N-diisopropyl)-phosphoramidite compd. suitable for use in normal nucleic acid chem. [on SciFinder(R)]

Abstract: The invention concerns biosensors for the detection of mols. that are composed of an array of immobilized supramol. structures that have non-covalent binding sites for the receptor mols.; the receptor mols. are selected in a manner that they recognize the target mols. and they are labeled; the receptors recognize the target mols. immunol.; the receptor mol. with the captured target is hybridized to the immobilized array of the biosensor. The hybridized complex can be detected by the sensor in various ways, e.g. by fluorescence, change in electrode potential etc. Changing thermodn. parameters, e.g. concn., temp., the hybridized receptor-target complex can be removed from the surface and used in further procedures. The immobilized binding mols. are nucleic acid derivs. that differ from those in biol. samples; e.g. pyranosyl nucleotides, and pyranosyl RNAs; the immobilized binding mols. can hybridize several types of receptor mols. The receptor mols. are chosen from chem. libraries, peptide libraries; several receptor mols. that recognize different parts of the target mols. are used; the recognizing peptide/protein part of the receptor is bound via linkers to the hybridizing part. The method can be used in combination with biochip techniques for drug screening, pesticide and herbicide research, for anal. and prodn. of catalysts. [on SciFinder(R)]

Abstract: Title compds. [(I); Base = (un)protected, (deaza)-purine or -pyrimidine; R = H, OH, Br, Cl; R1, R2 = (independently) H, protecting group], useful as non-interfering RNA/DNA supports for screening, were synthesized. Thus, N6-benzoyl-9-(2',3',4'-tri-O-benzoyl β-D-ribo-pyranosyl)-adenine was N,O-deprotected, N-dibenzoylated, 2'-O-benzoylated, 4'-dimethoxytritylated, and then 2'->3'-benzoyl-shifted to give p(entopyranosyl)-RNA-A-H I [stereo = β-D-ribo; Base = N6,N6-di-benzoyl-adenine; R = OH; R1 = COPh; R2 = DMT(II)]. II was used to synthesize the p-RNA-(A8)-H octamer, which was then condensed with 5'-H-dGATTC-H-3' to give 5'-H-dGATTC-(3'→4')-p-RNA-(A8)-H-2'. [on SciFinder(R)]

Abstract: Title compds. [(I, II); Base = (un)protected, (deaza)-purine or -pyrimidine; R = H, OH, Br, Cl; R1, R2 = (independently) H, protecting group], useful as linking groups between pentopyranosyl RNAs (p-RNA) and ribo-furanosyl RNA or DNA chains, were synthesized. Thus, pentopyranosyl-indole linker III was prepd. in six steps, starting from N-phthalimidotryptamine and D-ribose. III could be used as a linking group between a chain of p-RNA and ribo-furanosyl RNA or DNA chains (no data). [on SciFinder(R)]

Abstract: The invention relates to a compd. of formula (I), wherein R1 is NR3R4, OR3 or SR3 with R3 and R4 being H or CnH2n+1 independently of each other and being the same or different, n being a whole no. from 1 to 12; R2 is equal to CmH2m-C(X)-Y with X being =O, =S or =N, Y being equal to OR3, NR3R4 or SR3, R3 and R4 having the same meaning given above, and m being a whole no. from 1 to 4; or R2 is equal to CmH2m-Z-Y' with Z being a sulfonyl, phosphonyl, ether or amine group, Y' being equal to H, CnH2n+1, OR3, NR3R4 or SR3 then Z is sulfonyl or phosphonyl group, n, R3 and R4 having the meaning given above, and Y' being equal to CnH2n+1 when Z is an ether or an amine group; A, B, and D are the same or different and mean CR5R6, O, NR7 or S independently of each other with R5, R6 and R7 being H or CnH2n+1, independently of each other, n having the meaning given above; and C is equal to CR8 or N with R8 having the meaning of R5 independently, A-B, B-C or C-D not being two identical hetero-atoms; and nucleobase means thymine, uracil, adenine, cytosine, guanine, iso-cytosine, iso-guanine, xanthine or hypoxanthine. The invention also relates to a method for producing these derivs. and to their use in pairing and/or testing systems. These compds. are of interest because they form the building units of cyclohexylnucleooligoamides (CNAs), which have the ability to base-pair with natural DNAs or RNAs, without the steric considerations posed by the ribo- or deoxy-ribo-furan rings of natural (deoxy)nucleic acids. Thus, (S,S,S)-2-iodo-8-aza[3.3.1]nonan-7-one was reacted with 3-(benzyloxy)methyl-thymine, to yield, after a series of protection/deprotection steps, I [A, B, D = CH2; C = (S)-CH; Nucleobase = thymine; R1 = (S)-BOC-NH; R2 = (S)-CH2CO2H (II)]. Using II and the adenine-base equiv., CNAs up to hexamers were synthesized using solid-phase techniques, and their self-complimentary base-pairing strength was measured. [on SciFinder(R)]

Abstract: A facility and app. are described for monitoring of chem. test reactions in miniaturized reactors in parallel, in which the reactors can be analyzed with respect to the nature and degree of reaction and formation of products. The process, which involves reactors provided with inlet pipes and bypasses, and has reactors with vols. 0.001-1 cm3, is esp. useful for screening of potential catalysts and reactions under virtually identical and reproducible conditions and with a relatively low amt. of substance and samples, at low cost. The method also has application in combinatorial chem. [on SciFinder(R)]

Abstract: A method for simultaneous screening of a large no. of catalyst samples and microsamples consists of one or more high-vacuum chambers into which a solid is introduced that has a compd. or material ("educt") that desorbs from the solid support and enters the sample holding area. This desorbed educt then reacts with the catalyst samples, and the reaction products can be analyzed in a mass spectrometer (esp. a time-of-flight mass spectrometer). [on SciFinder(R)]

Abstract: The invention relates to a supramol. nanosystem contg. at least one substantially non-helical oligomer (oligomer A) and one or more identical or different, substantially non-helical oligomers which do not pair with each other, with identical or different functional units (oligomer B), in which the oligomer A can pair specifically non-covalently, and oligomer B is determinable by its monomers. In this system, the normal furano-sugars are replaced by pyrano-sugars. Such a system, by virtue of its ability to bind metal atoms on one or both oligomers, could form the basis of a nano-machine. The system also allows for prepn. of combinatorial libraries of sequences useful in screening tests. [on SciFinder(R)]

Abstract: The invention relates to a substance library, a process for the prodn. thereof, a process for the prodn. of supramol. complexes using said substance library, the use of said supramol. complexes produced using the substance library, and the use of the substance library itself. Uses claimed include use as medications, as plant protective materials, as catalysts, or as diagnostic material in treating illness. Thus, a cyclohexylnucleooligoamide (CNA) pentamer AATAT was synthesized, and coupled with amino acids to form a dipeptide library X-Lys-CNA(AATAT), where X = Ala, Asp, Leu, Lys, or Ser. [on SciFinder(R)]