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IPI-504 (retaspimycin hydrochloride) is an Hsp90 inhibitor that is the subject of multiple clinical trials for the treatment of cancer. IPI-504 is an aqueous soluble (>200 mg/ml) hydroquinone hydrochloride salt of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a quinone derivative also undergoing clinical evaluation, albeit with suboptimal formulations that address its inferior aqueous solubility (∼50 µg/ml). IPI-504 interconverts with 17-AAG in vivo through oxidation-reduction reactions that result in a dynamic redox equilibrium. The development challenges associated with redox active molecules are significant due to the pH, oxygen, and temperature sensitivities associated with such chemotypes. The API and sterile drug product manufacturing processes thus warrant the monitoring and control of these key variables. Furthermore, the pharmaceutical development challenges associated with cancer agents that are often fast-tracked due to unmet medical needs mandate a rapid development cycle with associated regulatory hurdles. Drug Dev Res 71: 429–438, 2010. © 2010 Wiley-Liss, Inc.

The N-dicyclopropylmethyl (Dcpm) residue, introduced into amino acids via reaction of dicyclopropylmethanimine hydrochloride with an amino acid ester followed by sodium cyanoborohydride or triacetoxyborohydride reduction, can be used as an amide bond protectant for peptide synthesis. Examples which demonstrate the amelioration of aggregation effects include syntheses of the alanine decapeptide and the prion peptide (106-126). Avoidance of cyclization to the aminosuccinimide followed substitution of Fmoc-(Dcpm)Gly-OH for Fmoc-Gly-OH in the assembly of sequences containing the sensitive Asp-Gly unit.

Of the three theoretically possible, Bsmoc-related, naphthothiophene sulfone-based amino-protecting groups, the two most readily available derivatives, the alpha- and beta-Nsmoc analogues, have been examined as substitutes for the Bsmoc residue in cases where the latter lead to oily protected amino acids or amino acid fluorides. All of the naphtho systems gave easily handled solid amino acid derivatives. The intermediate sulfone alcohol 11 used as the key reagent for introduction of the alpha-Nsmoc protecting group was readily made from alpha-tetralone (Scheme 1). The corresponding beta-analogue 17 was made similarly on a small scale, but due to the high cost of beta-tetralone, an alternate route involving reaction of rhodanine with alpha-naphthaldehyde was used for large-scale work (Scheme 2). All proteinogenic amino acids were converted to their alpha- and beta-Nsmoc derivatives. Deblocking studies showed that the reactivity toward deblocking by piperidine followed the order alpha-NsmocBsmocbeta-Nsmoc. 1H NMR experiments showed that deblocking of the two new systems was mechanistically similar to that previously established for the Bsmoc derivative in that the reaction is initiated by Michael addition to the beta-carbon atom of the alpha,beta-unsaturated sulfone system. Application of alpha- and beta-Nsmoc amino acids to the solid-phase synthesis of two model peptides was examined. An advantage of the alpha-Nsmoc system over the long-known Bsmoc system proved to be the milder conditions needed for the deblocking step relative to the Bsmoc case, which is itself more readily deblocked than the classic Fmoc analogue.

Clofarabine is a promising DNA polymerase inhibitor currently in clinical trials for a variety of liquid and solid tumor indications. The efforts for development of a new manufacturing process for clofarabine are presented. This new process allows for the reliable and efficient production of drug substance in high anomeric excess and high overall purity, without using chromatography. The high anomeric selectivity is achieved by reacting 2-chloroadenine with 1-bromo-2-deoxy-2-fluoro-3,5di-O-benzoyl-rD-ribofuranose (4) and potassium tert-butoxide in a mixture of three solvents. Following crystallization, anomeric ratios exceeding 50 (‚/r) are achieved. Deprotection and additional crystallization afford a clofarabine drug substance containing less than 0.1% of the r-anomer.

The Fmoc/TAEA and Bsmoc/TAEA methods for the rapid, continuous solution synthesis of peptide segments are shown to be applicable to the gram-scale synthesis of short peptides as well as, for the first time, to the synthesis of a relatively long (22-mer) segment, (hPTH 13−34). In the latter case the crude product was of significantly greater purity than a sample obtained via a solid-phase protocol. The Bsmoc methodology was optimized by a new technique involving filtration of the growing partially deprotected peptide at each coupling−deprotection cycle through a short column of silica gel.

Full details are presented for use of the Bsmoc amino-protecting group for both solid phase and rapid continuous solution syntheses. Application to the latter methodology represents a significant improvement over the corresponding Fmoc-based method for rapid solution synthesis due to the opportunity to use water or saturated sodium chloride solution rather than an acidic phosphate buffer to remove all byproducts, with consequent cleaner phase separation and higher yields of the growing peptide. Comparison of the Bsmoc and Bspoc functions showed that the former, because of steric hindrance, does not suffer from the competitive or premature deblocking observed with the Bspoc system. Because of its incorporation of a styrene chromophore, resin loading of Bsmoc amino acids could be followed as has previously been shown for the Fmoc analogues. Applications of Bsmoc chemistry to peptide sequences incorporating the base sensitive Asp-Gly unit gave less contamination due to aminosuccinimide formation than compara...

Although Fmoc amino acid fluorides are excellent reagents for coupling of moderately hindered amino acids ( e.g. , Aib-to-Aib) they are not suited for significantly more hindered systems ( e.g. , Aib-to-MeAib). While urethane-protected acid chlorides are inherently more reactive than the fluorides they are also ineffective for hindered systems due to competing oxazolone formation. This limitation is by-passed if urethane protection is replaced by arenesulfonyl protection and the Aib-to-MeAib and even the MeAib-to-MeAib couplings are easily achieved via the appropriate acid chlorides but not the acid fluorides.

A considerable amount of literature has investigated positive economic and social outcomes that learning may have both for individuals and for societies. Better-educated people typically have better health status, lower unemployment, more social connections, and greater engagement in civic and political life. This paper aims to explore the relationship between investments in education and research and the level of quality of life in a country. The investments in education and research are expressed in terms of expenditure on education and research, financial aid to pupils and students and public subsidies to private sector. For the assessment of quality of life there were considered three well-known composite indicators: Human Development Index, Economist Intelligence Unit Quality of Life Index, and Satisfaction with Life Scale. The analysis is done using data on European Union 27 member states, which come from Eurostat database and from specialized institutions’ sites. The study shows a positive relation between investments in education and quality of life. It identifies the annual expenditure on public and private educational institutions per pupil/student and the gross domestic expenditure on research and development as being the indicators of investments in education that best predict the level of quality of life in a country. Journal: Journal of Knowledge Management, Economics and Information Technology

Thermal condensations of penta-1,5-dien-3-ynes with two molecules of olefinic dienophiles proceed stereospecifically with retention of the configurations of the dienophiles, and with both molecules of the dienophile in each reaction adding to the same face of the dienyne.

Previously, 2,4,6-trimethylpyridine (collidine), due to steric shielding around the N-atom, was found to be an efficient base for effecting peptide segment coupling via azabenzotriazole-based onium-style coupling reagents. A number of even more highly hindered bases, including 2,3,5,6-tetramethylpyridine, 2,6-di-tert-butyl-4-(dimethylamino)pyridine, triisopropylamine, and N-tert-butylmorpholine, have been compared with collidine in such reactions. Some of the newer bases showed advantages in terms of convenience in handling and maintenance of configuration during segment coupling processes, although dramatic differences based on steric effects were not observed. On the basis of results with a number of test peptides and many base-coupling reagent combinations, it was noted that most efficient results are obtained if 1 equiv of HOAt is present as an additive during the coupling process. For rapid activation of onium-style coupling reagents during stepwise solid-phase coupling reactions, the stronger base 2...

A variety of 2-alkyl or (hetero)aryl thiazolo[4,5-c]quinolines have been efficiently synthesized by treatment of the amide derived from 3-amino-4-chloroquinoline with the appropriate O-ethyl thiocarbox-ylates. Diverses thiazolo[4,5-c]quinoleines substitutes en position 2 par des groupements alkyles ou (het-ero)aryles ont ete preparees par action de differents thioesters sur I'amidure derive de la 3-amino-4-chloroquinoleine.

[reaction: see text] Isolated Fmoc amino acid fluorides have previously been shown to be among the most efficient reagents for peptide bond formation. Now, it has been found that anionic, polyhydrogen fluoride additives are capable of diverting many of the classical peptide coupling processes to acid fluoride couplings. Examples include the use of N-HBTU or N-HATU and the carbodiimide technique. As HF-containing species, these additives provide a more suitable medium for the coupling of systems that are sensitive to loss of configuration at the reactive carboxyl function.

Vinylacetylene 1 undergoes reactions with dienophiles by a mechanism involving initial addition of acids to the triple bond, cycloaddition, and elimination of acid.

Vinylacetylene 1 undergoes reactions with dienophiles by a mechanism involving initial addition of acids to the triple bond, cycloaddition, and elimination of acid.

3-Substituted isoindolines have been efficiently prepared by sequential lithiation and reduction of isoindolinones.

Full details are presented for use of the Bsmoc amino-protecting group for both solid phase and rapid continuous solution syntheses. Application to the latter methodology represents a significant improvement over the corresponding Fmoc-based method for rapid solution synthesis due to the opportunity to use water or saturated sodium chloride solution rather than an acidic phosphate buffer to remove all byproducts, with consequent cleaner phase separation and higher yields of the growing peptide. Comparison of the Bsmoc and Bspoc functions showed that the former, because of steric hindrance, does not suffer from the competitive or premature deblocking observed with the Bspoc system. Because of its incorporation of a styrene chromophore, resin loading of Bsmoc amino acids could be followed as has previously been shown for the Fmoc analogues. Applications of Bsmoc chemistry to peptide sequences incorporating the base sensitive Asp-Gly unit gave less contamination due to aminosuccinimide formation than compara...

Fmoc amino acid fluorides have proven to be generally useful for peptide synthesis, even in the case of hindered systems such as those incorporating adjacent Aib residues. In such cases, Fmoc-Aib-F has been shown to be more efficient than the corresponding acid chloride (Fig. 1) because the urethane-protected amino acid chloride is converted much more readily than the acid fluoride to the corresponding oxazolone. On the other hand Fmoc-amino acid fluorides appear to have reached their limits in attempted applications to very highly hindered substrates, e.g. the coupling of Fmoc-protected proteinogenic amino acids to MeAib substrates. The corresponding amino acid chlorides, although long disregarded due to deficiencies associated with available protocols, can, in fact, overcome these limitations. In the presence of bis(trimethylsilyl)-acetamide (BSA), urethaneprotected amino acid chlorides provide for a far more efficient process than the corresponding fluorides (Fig. 1). By switching to other forms of that are more compatible with the acid chloride functionality such as N-arenesulfonyl protectants for which the already high reactivity of the acid chloride unit is increased by inductive effects, it is possible to couple Aib to MeAib units within a few minutes. Indeed it is even possible to couple MeAib to MeAib, a reaction never achieved previously. Because of its facile removal the Pbf group was used as Thus, Pbf-MeAib-Cl (1 eq.) was coupled to (2 eq.) in toluene in the presence of DIEA (2 eq.) and BSA (1 eq.) within 2-3 h in a 70% yield. The structure of the resulting dipeptide (Pbf-MeAib-MeAib-OMe), purified by preparative HPLC, was confirmed by NMR analysis, mass spectrometry, and CHN analysis. Removal of the Pbf-group by means of 10% dimethylsulfide in trifluoroacetic acid (v/v) for 1 h at ambient temperature yielded the desired dipeptide, MeAib-MeAibOMe, in a yield of 87%.

Publisher Summary This chapter discusses the use of novel coupling reagents for solid-phase peptide synthesis. Common coupling reagents used for the construction of peptide bonds include carbodiimides, N , N -dicyclohexylcarbodiimide (DCC) and N , N -diisopropylcarbodiimide (DIPCDI) for butyloxycarbonyl (Boc) and 9-fluorenylmethyloxycarbonyl (Fmoc) strategies, respectively, active esters such as pentafluorophenyl derivatives (OPfp) and uronium and phosphonium salts based on N -hydroxybenzotriazole (HOBt). Fmoc amino acid fluorides and urethane-protected N-carboxyanhydrides (UNCA's) are also efficient reagents for rapid peptide coupling under both solution and solid-phase conditions. l-hydroxy-7-azabenzotriazole (HOAt), HATU, PyAOP, HAPyU and tetramethyl fluoroformamidinium hexafluorophosphate (TFFH) are efficient coupling reagents for solution- and solid-phase peptide synthesis. These derivatives enhance reactivity, reduce racemization and are suited for peptides containing either natural or hindered amino acids. These reagents are compatible with both manual and automated batch and continuous-flow techniques.

3-Substituted isoindolines have been efficiently prepared by sequential lithiation and reduction of isoindolinones.

Nine analogues of methotrexate, in which the side chain is modified by replacement of the terminal glutamyl moiety with other amino acids, were synthesized from 2,4-diamino-6-(chloromethyl)pteridine. None of these compounds exhibited significant activity against L1210.