Ring-opening metathesis polymerization of steroid-conjugated norbornenes and gradual release of estrone from a polymer film
Introduction
Steroids are widely used both internally and externally as medicines because they have a variety of biological activities. Although steroid medicines have strong physiological activities, they often show strong side effects such as infectious disease, osteoporosis, diabetes mellitus, steroid withdrawal syndrome (e.g., corticosteroids), nausea, headaches, and certain types of cancers (e.g., sex hormones) [1], [2]. Therefore, it is of critical importance in therapeutic treatment to deliver a particular steroid in a sustained manner but with precisely controlled slow delivery [3], [4].
To control the release or delivery of bioactive agents such as antibiotics, anti-inflammatories, and steroid hormones, polymers are often used as a rate-controlling matrix [5], [6], [7], [8], [9], [10], [11]. As an example of a steroid delivery system in the 1970s to 1980s, the World Health Organization (WHO) developed a contraceptive device for vaginal insertion made of silicon rubber blended with steroids and coated with a membrane that controlled the release rate [12], [13]. Buntner et al. [11] and Brannon-Peppas and coworkers [14] reported lactide-based co-polymers in which progesterone or β-estradiol is physically encapsulated. The hormone is released from the polymer matrix as it gradually biodegrades. However, a high initial rate of release is usually observed, which is attributed to the presence of drug molecules physically attached to the surface of the matrix particles.
Recently, a new type of bioactive polymer with pendant bioactive molecules has been developed based on the ring-opening metathesis polymerization (ROMP) of the corresponding monomers [15]. The ROMP of norbornene (NB) derivatives has been commonly used because the strained double bond of NB allows polymerization to occur even when it bears a very sterically demanding substituent such as bioactive residues. In these therapeutic polymers, each of the drug moieties is expected to efficiently interact with a ligand at a cell surface. Grubbs et al. reported the synthesis of homo- and co-polymers of NB derivatives with a conjugated oligopeptide (Gly-Arg-Gly-Glu-Ser; GRGDS) [16], and the resulting oligopeptide-substituted poly(NB)s were shown to be more bioactive than the free GRGDS peptide with respect to its inhibitory effect on cell adhesion to fibronectin [17]. Kiessling et al. studied the interaction of neoglycopolymers with cell surfaces and found that synthetic glycoprotein polymer promoted cell surface L-selectin shedding [18], [19]. Likewise, poly(NB) with covalently bound vancomycin was reported to exhibit enhanced antibacterial activities [20]. While these examples demonstrate synthetic approaches to bio-macromolecules, such polymers with pendant bioactive molecules may also be useful as a high-density drug-delivery system if the drug molecules can be cleaved from the polymer backbone under appropriate biological conditions. Gnanou and coworkers [21] and Nguyen and coworkers [22], [23] synthesized poly(NB)-based co-polymers with indomethacin and doxorubicin molecules bound through a carbamate or amide linkage. Co-polymers have been designed to form nano-particles and release drug molecules in acidic aqueous solutions. Although we might expect that chemically bound bioactive molecules can be released in a more controlled manner than physically blended or encapsulated bioactive agents, examples of this type of delivery system are still rare. In particular, to the best of our knowledge, the release of chemically bound drug molecules from solid-film surfaces has not been studied, presumably because not all bioactive polymers can form films. We report here unique monomers derived by ester bond formation between a series of steroids and NB derivatives, as well as their ROMP by a ruthenium–carbene complex (Grubbs second-generation catalyst, G-2) and a ruthenium–vinylidene complex (Ru–v). We also describe the hydrolysis of the ester bond under mild conditions at the surfaces of films that were immersed in acidic aqueous solutions, which resulted in the slow release of the original steroid (estrone) unit from the solid-film surface.
Section snippets
General
Melting points (m.p.) were determined on an electric micro hot stage Yanaco MP-500D (Kyoto, Japan) and were uncorrected. Infrared (IR) spectra were obtained on a JASCO FT-IR 4100 spectrometer (Tokyo, Japan) using the KBr disk method. Proton (1H) and carbon (13C) NMR spectra were obtained on a JEOL JNM-EX 270 MHz instrument (Tokyo, Japan) at 270 and 67.8 MHz, respectively, with CDCl3 containing 0.1% Me4Si as the solvent unless otherwise stated. In this paper, chemical shifts are expressed as δ
Synthesis of steroid-conjugated NB monomers (1–7)
Estrone (a) and β-estradiol (b) (Fig. 1), which are typical steroid hormones, were reacted with norbornene carboxylic acid chloride (I) in pyridine at room temperature. After purification by column chromatography, the estrone-NB monomer (1, Fig. 2) was obtained as a colorless amorphous solid with 60% yield. A similar solid of the estradiol-NB monomer (2) was obtained with a much lower yield (20%), apparently due to the two OH groups present in estradiol. Despite the careful slow addition of
Conclusion
New norbornene derivatives were prepared based on esterification reactions with steroids (estrone, estradiol, ursodeoxycholic acid, chenodeoxycholic acid, cortisone, prednisone, and dexamethasone). The ROMP of these sterically demanding monomers were carried out with the Grubbs second-generation catalyst. A ruthenium-vinylidene complex was also useful to initiate the ROMP under heating conditions. Polymer films could be prepared, with the exception of the prednisone derivative, by casting
Acknowledgements
This work was supported in part by a Nihon University Multidisciplinary Research Grant for 2007–2008, a Research Project of The Institute of Natural Sciences Nihon University in 2009, a Grant-in-Aid for Scientific Research from the Ministry of Education, Sciences, Sports, and Culture of Japan for 2007–2008 (Grant 19,510,223), and a Research for Promoting Technological Seeds Grant for 2007. We thank Mr. Y. Otsuka (TA Instruments) for the Tg and Td measurements.
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The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2010
2012, Coordination Chemistry ReviewsCitation Excerpt :The strained alkene norbornene, norbornene derivatives, and copolymerization involving a norbornene derivative and another alkene accounted for a large fraction of all reports of the ROMP reaction in 2010; representative monomers are depicted in Fig. 3. Numerous substituted norbornenes have been subjected to ROMP using metal carbene complexes, including those possessing the following structural features: (1) norbornenes or alkylnorbornenes [289,290]; (2) norbornenes followed by end-capping with alkenes connected to H-bonding groups [291]; (3) linkage to a cyclic carbonate group [292]; (4) linkage to chondroitin sulfate proteoglycans [293]; (5) linkage to a phenanthroline-terbium complex (55) [294]; (6) linkage to a zinc porphyrin system [295], (7) dinorbornenes (e.g. 54) [296–298]; (8) fusion to cyclohexane ring systems [299]; (9) tris(pyrollidinonorbornenes) [300] and norbornenepyrrolidines linked to hexabenzocoronenes [301]; (10) fusion to a cyclic phosphate ring (e.g. 56) [302]; (11) norbornadienes [303]; (12) dicyclopentadiene [304]; (13) norbornenemethanol derivatives [305–308]; (14) norbornenedimethanol derivatives connected to α-haloester groups that can initiate a radical polymerization [309]; (15) norbornenecarboxylate esters (e.g. 57) [310–319]; (16) optically active norbornenecarboxylate esters [320]; (17) linkage to a tris(phenylpyridyl)iridium(III) system via an ester group [321]; (18) norbornenes spiro-fused to Meldrum's acid (e.g. 58) [322]; (19) norbornene-dicarboxamides and norbornene-dimethanol derivatives linked to amino acid groups (e.g. 59) [323]; (20) norbornenesuccinimides [324–328], including those linked to a ruthenium tris(bipy) system [329], polyethylene glycol through a triazole group [330], photochromic groups [331], and various anticancer drugs via a triazole group [332]; (21) norbornenesuccinimides and norbornenecarboxylate esters using catalysts attached to H-bonding recognition elements [333]; (22) norbornenesuccinimides and norbornenesuccinic anhydrides [334,335]; (23) norbornenedicarboxylate esters [336–340]; (24) norbornenedimethanol and norbornenecarbonitrile [341]; (25) oxanorbornenecarboxylate esters [342,343]; (26) oxanorbornenesuccinimides [344], including those linked to oligomeric silsesquioxanes [345] and carboranes [346]; (27) oxanorbornenesuccimides followed by either end capping or cross metathesis [347]; (28) oxanorbornenedicarboxylate esters [348]; (29) oxanorbornenedicarboxylate ester and end capping via cross metathesis with cis 2-buten-1,4-diol esters [349]; and (30) bis(trimethylsilyl)substituted norbornenecyclobutanes (e.g. 60) [350]. Other ring systems that have been subjected to ROMP reactions include: (1) cyclobutenecarboxylate esters and amides (e.g. 61) [351,352]; (2) cyclooctene [353–357]; (3) cyclopentenes and cyclooctenes [358]; (4) cyclooctadiene [359–361]; (5) cyclooctenediol [362]; (6) cyclooctenenitriles [363]; (7) ammonium salt-linked bis(cyclooctenes) (e.g. 62) [364]; (8) cyclooctene derivatives followed by end-capping through cross metathesis with N-undecenylphthalane [365] or cis 1,4-diacetoxy-2-butene [366]; (9) ionic and non-ionic cyclooctatetraene derivatives (copolymerization) (e.g. 63 and 64) [367]; (10) a divinylthiophene cyclic oligomer (65) [368]; (11) dioxepins (e.g. 66) (or norbornenesuccinimides) and termination via vinylene carbonate or furanone [369]; (12) macrocycle-bridged steroids [370]; (13) p-cyclophanes (e.g. 67) [371]; and (13) macrocyclic amine-bis(lactones) (the monomer was prepared via RCM) [372].
Application of olefin metathesis in the synthesis of steroids
2011, SteroidsCitation Excerpt :The thermal and liquid crystalline properties of the homopolymers were investigated by different techniques [78]. Other steroids (estrone, estradiol, ursodeoxycholic acid, chenodeoxycholic acid, cortisone, prednisone, and dexamethasone) were also reacted with either 5-norbornene-2-carboxylic acid chloride or 5-norbornene-2-methanol to form norbornene derivatives with bioactive steroid residues bound with an ester linkage [79]. These norbornene based monomers were polymerized by a ring-opening metathesis polymerization initiated by the Grubbs’ II catalyst or the ruthenium–vinylidene complex (Fig. 4).
ROMP polymer-based antimicrobial films repeatedly chargeable with silver ions
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2016, Handbook of Maleic Anhydride Based Materials: Syntheses, Properties and Applications
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Present address: Central Research, Bridgestone Co., Kodaira-shi, Tokyo 187-8531, Japan.