Synthesis and Characterization of Thermally and Chemically Gelling Injectable Hydrogels for Tissue Engineering

Novel, injectable hydrogels were developed that solidify through a dual-gelation, physical and chemical, mechanism upon preparation and elevation of temperature to 37°C. A thermogelling, poly(N-isopropylacrylamide)-based macromer with pendant epoxy rings and a hydrolyticallydegradable polyamidoamine-based diamine crosslinker were synthesized, characterized, and combined to produce in situ forming hydrogel constructs. Network formation through the epoxyamine reaction was shown to be rapid and facile, and the progressive incorporation of the hydrophilic polyamidoamine crosslinker into the hydrogel was shown to mitigate the often problematic tendency of thermogelling materials to undergo significant post-formation gel syneresis. The results suggest that this novel class of injectable hydrogels may be attractive substrates for tissue engineering applications due to the synthetic versatility of the component materials and beneficial hydrogel gelation kinetics and stability

Cervical Mucus Properties Stratify Risk for Preterm Birth

Background: Ascending infection from the colonized vagina to the normally sterile intrauterine cavity is a well-documented cause of preterm birth. The primary physical barrier to microbial ascension is the cervical canal, which is filled with a dense and protective mucus plug. Despite its central role in separating the vaginal from the intrauterine tract, the barrier properties of cervical mucus have not been studied in preterm birth. Methods and Findings: To study the protective function of the cervical mucus in preterm birth we performed a pilot case-control study to measure the viscoelasticity and permeability properties of mucus obtained from pregnant women at high-risk and low-risk for preterm birth. Using extensional and shear rheology we found that cervical mucus from women at high-risk for preterm birth was more extensible and forms significantly weaker gels compared to cervical mucus from women at low-risk of preterm birth. Moreover, permeability measurements using fluorescent microbeads show that high-risk mucus was more permeable compared with low-risk mucus. Conclusions: Our findings suggest that critical biophysical barrier properties of cervical mucus in women at high-risk for preterm birth are compromised compared to women with healthy pregnancy. We hypothesize that impaired barrier properties of cervical mucus could contribute to increased rates of intrauterine infection seen in women with preterm birth. We furthermore suggest that a robust association of spinnbarkeit and preterm birth could be an effectively exploited biomarker for preterm birth prediction.Massachusetts Institute of Technology. Charles E. Reed Faculty Initiative FundBurroughs Wellcome Fund (Preterm Birth Research Grant)National Science Foundation (U.S.). Graduate Research Fellowship Progra

Feasibility of polymer-drug conjugates for non-cancer applications

Polymer-drug conjugates have been intensely studied in the context of improving cancer chemotherapy and yet the only polymer-drug conjugate on the market (MovantikÒ) has a different therapeutic application (relieving opioid-induced constipation). In parallel, a number of studies have recently been published proposing the use of this approach for treating diseases other than cancer. In this commentary, we analyse the many and very diverse applications that have been proposed for polymer-drug conjugates (ranging from inflammation, to cardiovascular diseases) and the rationales underpinning them. We also highlight key design features to be considered when applying polymer-drug conjugates to these new therapeutic areas

Design, Synthesis, and Testing of a Molecular Truck for Colonic Delivery of 5-Aminosalicylic Acid

A molecular scaffold bearing eight terminal alkyne groups was synthesized from sucrose. Eight copies of an azide-terminated, azo-linked precursor to 5-aminosalicylic acid were attached to the scaffold via copper(I)-catalyzed azide–alkyne cycloaddition. The resulting compound was evaluated in a DSS model of colitis in BALB/c mice against sulfasalazine as a control. Two independent studies verified that the novel pro-drug, administered in a dose calculated to result in an equimolar 5-ASA yield, outperformed sulfasalazine in terms of protection from mucosal inflammation and T cell activation. A separate study established that 5-ASA appeared in feces produced 24–48 h following administration of the pro-drug. Thus, a new, orally administered pro-drug form of 5-aminosalicylic acid has been developed and successfully demonstrated

Synthesis and characterization of fourth generation polyester-based dendrimers with cationic amino acids-modified crown as promising water soluble biomedical devices

Dendrimers are nanostructured \u201carchitectural motifs\u201d which fascinate researchers fortheir several potentiality due to well\u2010tailored structure, symmetric tree\u2010like shape,and abilities in entrapping or binding hydrophilic or hydrophobic entities such asgenetic materials, drugs, and target molecules. Nowadays dendrimers inhabit thetop places among the materials suitable for biomedical applications as drug delivery,gene transfection, and imaging. In this work, we report the design and realization oftwo versatile successful procedures to decorate a fourth generation polyester\u2010baseddendrimer matrix with a mixture of four different amino acids. The hydrochloridedendrimers achieved after removal of protecting groups were characterized by acore\u2010shell structure. They harmonized a not charged hydrolysable inner matrixpotentially able to accommodate hydrophobic molecules and a cationic highlyhydrophilic crown conferred by biocompatible amino acids that provided very satis-factory buffer capacity and will allow easy host/guest electrostatic interactions.Their structures and peripheral composition were confirmed by NMR analysis andexperimental molecular weight computed by volumetric titration, while their buffercapacity was obtained by potentiometric titrations. Because in the inner matrix, theachieved hetero dendrimers do not present the high density of positive chargestypical of PAMAM, they ensure a lower level of toxicity. But thanks to the cationicperiphery, as preliminary investigations still in progress have already put in evidence, they were able to entrap not water soluble molecules by electrostatic inter-actions, with the result to increase their water solubility in a very satisfactory oramazing way. They therefore represent two new very promising devices for bio-medical applications

Revisit: The Synthesis of 3-amino pyrazoles promoted by p-toluenesulfonic acid as an efficient catalyst under solvent and solvent-free conditions

An efficient and facile synthesis of 3-amino pyrazoles has been described. The reaction of b-keto nitriles with hydrazines using p-toluenesulfonic acid as an efficient catalyst under solvent and solvent-free conditions afford corresponding 3-amino pyrazoles in excellent yields&#x0D; Introduction&#x0D;  Pyrazoles, in particular 3-amino pyrazoles are an important class of compounds in medicinal chemistry and it has been well documented to posses antihypertensive,1 antibacterial,2 anti-inflammatory muscle relaxant3,4 and inhibitors of cyclin dependent kinases (CDK) such as CDK2/cycling A-E.5 They are also potent and selective Aurora kinase inhibitors.6,7 In addition the 3-amino pyrazoles also have industrial appliance in inhibition of corrosion on metals such as Zn, Cu, Al and Brass.8&#x0D; Despite their importance from a pharmacological, industrial and synthetic point of view, comparatively few methods for the preparation of 3-amino pyrazoles have been reported. These includes condensation of hydrazines with β-keto nitriles,9 β-formyl nitriles,4 β-methoxy vinyl nitriles,10 α-nitrilo ethyl acetate11 and solid phase synthesis of 5-substituted amino pyrazoles.12  Unfortunately many of these processes suffer from one or other limitations such as incompletion of starting materials, long reaction times, with unsatisfactory yields. Thus there is a need for the development of an alternate route to construct the 3-amino pyrazoles.&#x0D; In recent years, p-toluenesulfonic acid is used as an efficient catalyst in various organic transformations,13 also it should be noted that p-toluenesulfonic acid is cheap, commercially available and comparatively non-toxic. The organic reactions assisted by microwaves,14 in particular have been gained special attention. One reason is that the use of microwave activation in organic synthesis can increase the purity of the resulting products, enhance the chemical yield and shorten the reaction times. And also organic reactions carried out in the absence of solvent, has been attracting attention of chemists due to ease of processing to the further step and eco-friendly in nature. In the case of synthesis of 3-amino pyrazoles, we thought that there is a scope for further innovation towards short reaction times and better yields. Here, we report an efficient and facile method for the synthesis of 3-amino pyrazoles catalyzed by p-toluenesulfonic acid under solvent and solvent-free conditions.&#x0D; Scheme 1&#x0D; Results &amp; discussion &#x0D; Reaction of benzoyl acetonitrile i. e. b-keto nitrile15 with 4-hydrazinobenzoic acid under reflux conditions in absolute ethanol for 8-10hr resulted in the formation of the corresponding 3-amino pyrazoles in &lt;90% yield. However, we carried out the reaction in presence of catalytic amounts of p-toluenesulfonic acid (0.01 equiv.) and found reaction is completed in 45 min with nearly 100% conversion (Table 1, entry 7). This success has encouraged us to extend the generality of the reaction; various hydrazines with various b-keto nitriles in presence p-toluenesulfonic acid proceeded efficiently and smoothly at refluxing temperature and the products are obtained in excellent yields. And the reaction conditions are very favorable, no by-products are observed (Table 1, Method A).&#x0D; We further investigated the reaction conditions to improve the reaction conditions. It has been found that, b-keto nitrile 1 (1 mmol) and hydrazine 2 (1 mmol) reacts very rapidly (&lt;5min) to give 3-amino pyrazoles in the presence of p-toluenesulfonic acid under microwave irradiation in solvent-free conditions (Table 1, Method B). The experimental procedure for this reaction is remarkably simple and no solvents or inert atmosphere is required. Under above conditions, in many cases it is noticed that in the absence of p-toluenesulfonic acid, the reaction is incomplete and uncyclized product was isolated along with pyrazole.&#x0D; &#x0D; Table 2: Synthesis of 3-Amino pyrazole catalyzed by p-toluenesulfonic acid under solvent and solvent free conditions. &#x0D; a Isolated yields after crystallization/column chromatography and all products gave satisfactory spectral (IR, 1HNMR and MASS) and analytical data&#x0D;  &#x0D; In summary, the present procedures for the synthesis of 3-amino pyrazole have been developed by condensation reaction of hydrazines with b-keto nitriles catalyzed by p-toluenesulfonic acid under solvent and solvent free conditions. The advantage of present method is high efficient, reduced reaction time and inexpensive catalyst with high yields of products and simple experimental work-up procedure, which makes it, is a useful and important addition to the present existing methodologies.&#x0D; Acknowledgements: The authors are thankful to Director IICT for his constant encouragement and DOD New Delhi for providing fellowship.&#x0D; Typical Experimental procedure (Method A, Conventional): A mixture of b-keto nitile (10 mmol), hydrazine (10 mmol) and to this p-TSA (0.1mmol) was added and refluxed in absolute ethanol for appropriate time (Table 1, Method A). After completion of the reaction, as monitored by TLC, the solvent was evaporated under reduced pressure. The product was extracted into ethyl acetate (3 x 20 mL). The combined organic layer was washed with saturated sodium bicarbonate followed by brine solution, then dried over anhydrous sodium sulphate. The solvent was removed to afford crude product and purified by column chromatography.&#x0D; Typical Experimental procedure (Method B, Microwave): A mixture of b-keto nitile (10 mmol), hydrazine (10 mmol), p-TSA (0.1mmol) was suspended in water (1mL) in a reaction vessel, sealed without degassing and was subjected to microwave irradiation at 450Watt. at 1350C for appropriate time (Table 1, Method B). After completion of the reaction, as monitored by TLC, the reaction mass was cooled and product was extracted into ethyl acetate (3 x 20 mL). The combined organic layer was washed with saturated sodium bicarbonate followed by brine solution, then dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to afford crude product, it was purified by recrystallized from ethanol/column chromatography to give corresponding pure 3-amino pyrazoles.&#x0D; 3a: IR (KBr): 3418, 1618, 1509, 1009, 762, 707 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 1.25 (s, 9H), 5.85 (s, 1H); EIMS: m/z 139; Anal. Calcd. for C7H13N3: C, 60.431; H, 9.352; N, 30.215. Found: C, 60.399; H, 9.412, N, 30.186.&#x0D; 3b: IR (KBr): 3420, 1620, 1520, 750 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 2.26 (s, 3H), 4.75 (s, 2H br), 7.40 (s, 5H); EIMS:  m/z 173; Anal. Calcd. for C10H11N3: C, 69.280; H, 6.350; N, 24.277. Found: C, 69.340; H, 6.401, N, 24.258.&#x0D; 3c: IR (KBr): 3415, 1618, 1124, 613 cm-1; 1H NMR (200 MHz, DMSO+CDCl3) δ 4.25 (s, 2H br.), 5.75 (s, 1H), 7.30 (m, 5H); EIMS: m/z 157; Anal. Calcd. for C9H9N3: C, 67.924; H, 5.660; N, 26.415. Found: C, 67.905; H, 5.698, N, 26.396.&#x0D; 3d: IR (neat): 3448, 1636 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 5.5 (s, 1H), 7.25 (d, 2H, J = 8.25Hz), 7.35 (d, 2H, J = 8.25Hz); EIMS: m/z 193, 195; Anal. Calcd. for C9H8ClN3: C, 55.958; H, 4.145; Cl, 18.393; N, 21.761. Found: C, 55.826; H, 4.164; Cl, 18.308; N, 21.700.&#x0D; 3e: IR (KBr): 3413, 1618, 1511, 1108, 613 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 2.50 (s, 3H), 5.95 (s, 1H), 7.45 (d, 2H, J = 8.20Hz), 7.75 (d, 2H, J = 8.20Hz); EIMS: m/z 173. Anal. Calcd. for C10H11N3: C, 69.364; H, 6.358; N, 24.277. Found: C, 69.340; H, 6.401; N, 24.258.&#x0D; 3f: IR (KBr): 3415, 1694, 1615, 1179, 616 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 5.68 (s, 1H), 6.41 (s, 1H), 6.59 (s, 1H), 7.4 (s, 1H); EIMS: m/z 149; Anal. Calcd. for C7H7N3O: C, 56.375; H, 4.697; N, 28.187; O, 10.738. Found: C, 56.369; H, 4.730; N, 28.173; O, 10.736.&#x0D; 3g: IR (KBr): 3414, 1616, 1091 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 6.60 (s, 1H), 7.40 (m, 5H), 7.8 (d, 2H, J = 8.50Hz), 8.40 (d, 2H, J = 8.50Hz); EIMS: m/z 279; Anal. Calcd. for C16H13N3O2: C, 68.817; H, 4.659; N, 15.053; O, 11,469. Found: C, 68.806; H, 4.691; N, 15.044; O, 11.456.&#x0D; 3h: IR (KBr): 3414, 1617, 1383, 618 cm-1; 1H NMR (200 MHz, DMSI+CDCl3): δ 5.9 (s, 1H), 7.15 (m, 5H), 7.35 (d, 1H, J = 8.15Hz), 7.60 (t, 1H, J = 3.15Hz), 7.85 (d, 1H, J = 8.25Hz), 7.9 (d, 1H, J = 8.15Hz), 8.30 (s, 1H); EIMS: m/z 279; Anal. Calcd. for C16H13N3O2: C, 68.817; H, 4.659; N, 15.053; O, 11.469. Found: C, 68.806; H, 4.691; N, 15.044; O, 11.456.&#x0D; 3i: IR (KBr): 3415, 1618, 1285, 761 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 1.25 (t, 3H), 3.90 (q, 2H), 6.25 (s, 1H), 7.40 (m, 5H), 7.7 (d, 2H, J = 8.25Hz), 8.05 (d, 2H, J = 8.25Hz); EIMS: m/z 313;&#x0D; 3j: IR (KBr): 3415, 1657, 1615, 1384, 1121, 758 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 1.25 (t, 3H), 4.25 (q, 2H), 4.925 (s, 2H), 5.85 (s, 1H), 7.5 (m, 5H); EIMS: m/z 245; Anal. Calcd. for C13H15N3O2: C, 63.673; H, 6.122; N, 17.142; O, 13.067. Found: C, 63.658; H, 6.164; N, 17.131; O, 13.045.&#x0D; 3k: IR (KBr): 3416, 1650, 1384, 1120, 758 cm-1; 1H NMR (200 MHz, DMSO+CDCl3) δ 6.02 (s, 1H), 7.15 (d, 2H, J = 8.15Hz), 7.35 (d, 2H, J = 8.23Hz), 7.60 (d, 2H, J = 8.15Hz), 8.10 (d, 2H, J = 8.23Hz); EIMS: m/z 303, 305; Anal. Calcd. for C16H12ClN3O2: C, 61.341; H, 3.833; Cl, 11.341; N, 13.415; O, 10.223. Found: C, 61.252; H, 3.855; Cl, 11.299; N, 13.393; O, 10.198.&#x0D; 3l: IR (KBr): 3415, 1650, 1090 cm-1; 1H NMR (200 MHz, DMSO+CDCl3) δ 6.8 (s, 1H), 7.4 (d, 2H, J = 8.15Hz), 7.6 (t, 1H, J = 3.00Hz), 7.8 (d, 3H, J = 8.25Hz), 8.1 (d, 1H, J = 8.25Hz), 8.3 (s, 1H, J = 8.15Hz), 9.93 (s, 1H); EIMS: m/z 303, 305; Anal. Calcd. for C16H12ClN3O2: C, 61.341; H, 3.833; Cl, 11.341; N, 13.415; O, 10.223. Found: C, 61.252; H, 3.855; Cl, 11.299; N, 13.393; O, 10.198.&#x0D; 3m: IR (KBr): 3415, 1617, 1384, 764, 619 cm-1; 1H NMR (200MHz, DMSO+CDCl3) δ 2.37 (s, 3H), 3.75 (s, 2H broad), 7.1 (d, 2H, J = 8.22Hz), 7.4 (d, 2H, J = 8.15Hz), 7.7 (d, 2H, J = 8.15Hz), 8.0 (d, 2H, J = 8.22Hz); EIMS: m/z 291; Anal. Calcd. for C17H15N3O2: C, 69.624; H, 5.119; N, 14.334; O, 10.921. Found: C, 69.611; H, 5.154; N, 14.325; O, 10.908.           &#x0D; 3n: IR (KBr): 3415, 1618, 1384, 1216, 1047, 816, 619, 476 cm-1; 1H NMR (200 MHz, DMSO+CDCl3) δ 1.25 (t, 3H), 2.50 (s, 3H), 3.90 (q, 2H), 6.25 (s, 1H), 7.1 (d, 2H, J = 8.25Hz), 7.6 (d, 2H, J = 8.25Hz), 7.7 (d, 2H, J = 8.15Hz), 8.1 (d, 2H, J = 8.15Hz); EIMS: m/z 328; Anal. Calcd. for C17H17N3O2­­­­­­­­S: C, 62.385; H, 5.198; N, 12.84; O, 9.785; S, 9.785. Found: C, 62.365; H, 5.233; N, 12.834; O, 9.773; S, 9.793.&#x0D; 3o: 1H NMR (200 MHz, DMSO+CDCl3): δ 1.26 (s, 9H), 5.95 (s, 1H), 7.60 (d, 2H, J = 8.80Hz), 8.50 (d, 2H, J = 8.80Hz); EIMS: m/z 260.&#x0D; 3p: 1H NMR (200 MHz, DMSO+CDCl3): δ 2.26 (s, 3H), 7.40 (s, 5H), 7.62 (d, 2H, J = 8.60Hz), 8.56 (d, 2H, J = 8.60Hz); EIMS:  m/z 294.&#x0D; 3q: 1H NMR (200 MHz, DMSO+CDCl3) δ 5.75 (s, 1H), 7.30 (m, 5H), 7.66 (d, 2H, J = 8.30Hz), 8.46 (d, 2H, J = 8.30Hz); EIMS:  m/z 280.&#x0D; 3r: 1H NMR (200 MHz, DMSO+CDCl3): δ 5.5 (s, 1H), 7.26 (d, 2H, J = 8.25Hz), 7.36 (d, 2H, J = 8.25Hz), 7.68 (d, 2H, J = 8.20Hz), 8.49 (d, 2H, J = 8.20Hz); EIMS:  m/z 314.&#x0D; 3s: 1H NMR (200 MHz, DMSO+CDCl3): δ 2.50 (s, 3H), 6.05 (s, 1H), 7.55 (d, 2H, J = 8.26Hz), 7.76 (d, 2H, J = 8.55Hz), 7.80 (d, 2H, J = 8.26Hz), 8.49 (d, 2H, J = 8.55Hz); EIMS:  m/z 294.&#x0D; 3t: IR (KBr): 3425, 1694, 1615, 1500, 1485, 1425, 1179, 616 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 5.75 (s, 1H), 6.46 (s, 1H), 6.65 (s, 1H), 7.4 (s, 1H), 7.66 (d, 2H, J = 8.30Hz), 8.46 (d, 2H, J = 8.30Hz); EIMS:  m/z 270; Anal. Calcd. for C13H10N4O3: C, 57.77; H, 5.119; N, 20.74; O, 17.77. Found: C, 57.78; H, 3.73; N, 20.73; O, 17.76.&#x0D;  &#x0D; References:&#x0D; &#x0D; Almansa, L. A. Gomez, F. L Cavalcanti, A. F. de Arriba, J. Garcia-Rafanell, J. Form, J. Med. Chem., 1997, 40, 547.&#x0D; Daidone, B. Maggio, S. Plescia, D. Raffa, C. Musiu, C. Milia, G. Perra, M. E. Marongiu, Eur. J. Med. Chem., 1998, 33, 375; J. Finn, K. Mattia, M. Morytko, S. Ram, Y. Yang, X. Wu, E. Mak, P. Gallant, D. Keith, Bioorg. Med. Chem. Lett., 2003, 13, 2231.&#x0D; D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter, P. R. Collins, S. Docter, M. J. Graneto, L. F. Lee, J. W. Malecha, J. M. Miyashiro, R. S. Rogers, D. S. Rogier, S. S. Yu, G. G. Anderson, E. G. Burton, J. N. Cogburn, S. A. Gregory, C. M. Koboldt, W. E. Perkins, K. Seibert, A. W. Veenhuizen, Y. Y. Zhang, P. C. Isakson, J. Med. Chem., 1997, 40, 1347; S. Zhihua, J. Guan, F. P. Michael, M. Kathy, W. P. Michael, M. V. William, S. Monica, S. Michele, R. M. Dave, C. 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Electro Chem., 1989, 19, 928; W. A. Badawy, M. M. Hefny, S. S. El-Egany, Corrosion, 1990, 46, 978; M. M. Abou-Romia, H. A. Abd El-Rahaman, H. A. M. El-Sayed, Bull. Electrochem., 1990, 6, 757.&#x0D; Jagath Reddy, D. Latha, K. Srinivasa Rao, Org. Prep. Proced., 2004, 36, 494; K. C. Joshi, V. N. Pathak, U. Garg, J. Het. Chem., 1979, 16, 1141.&#x0D; Hanefeld, C. W. Rees, A. J. P. White, J. Chem. Soc., Perkin Trance-I, 1996, 1545&#x0D; Vanotti, F. Fiorentini, M. Villa, J. Het. Chem., 1994, 31, 737.&#x0D; S. Dodd, R. L. Martinez, M. Kamau, Z. Ruam, K. V. Kirk, C. B. Cooper, M. A. Hermsmeier, S. C. Traeger, M. A. Poss, J. Comb. Chem., 2005, 7, 584. .&#x0D; R. Khospour, M. M. Kodhoaei, H. Monghannian, Synlett, 2005, 955; A. R. Khospour, K. Esmaeilpoor, A. Moradie, J. Iran. Chem. Soc., 2006, 3, 81; G. Shanmugam, M. Madhavi, P. Anil Kumar, M. Prabhakahr, N. Venu, S. Venkataraman, T. M. Vijayavitthal, G. Mahesh Reddy, Y. Ravindra Kumar, Chemlform, 2005, 36, 46.&#x0D; Larhed, A. Halberg, J. Org. 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Will Catalysts Save Our Environment?

If you own a car, then at some point in your life, you’ll end up having to go to the mechanic to address any emergent car troubles. You may experience engine troubles, slower acceleration, or smoke coming out of your car’s exhaust, only to find out that you have a “bad cat.” What do these cute little furballs have to do with cars?</jats:p