Uses for Akanocure Stereotetrad Lactones 4: lactone openings with sulfur nucleophiles

One of PolySciTech’s latest product offerings is Akanocure stereotetrad lactones (https://akinainc.com/polyscitech/products/akanocure/index.php) for use as synthetic precursors. There are many potential reactions for these lactones which can result in a wide array of useful molecules. In this series of postings, we will highlight potential uses of these materials. One potential reaction is the ring-opening of the lactone using sulfur (thiol) nucleophiles. Recently, this reaction has been applied to the synthesis of peloruside A, a potent chemotherapeutic agent. This research holds promise for improved availability of advanced chemotherapeutic agents. Read more: Raghavan, Sadagopan, and V. Vinoth Kumar. “A stereoselective synthesis of the C9–C19 subunit of (+)-peloruside A.” Organic & biomolecular chemistry 11, no. 17 (2013): 2847-2858. http://pubs.rsc.org/en/content/articlelanding/2013/ob/c3ob27508f#!divAbstract

“Abstract: The stereoselective synthesis of a C9–C19 fragment of the potent antitumor agent peloruside A is disclosed. The C11 stereogenic centre was created by a vinylogous Mukaiyama aldol reaction following Carreira’s protocol, with excellent stereocontrol. The C13 stereogenic centre was introduced by a substrate controlled reduction. The C15 stereocentre was fashioned using Noyori’s asymmetric transfer hydrogenation while the Z-trisubstituted double bond was formed by a regioselective hydrostannation of an alkyne followed by methylation of the resultant vinyl stannane using Lipshutz’s protocol. The C18 chiral centre was introduced by a chemoenzymatic route.”

Uses for Akanocure Stereotetrad Lactones 3: lactone openings with secondary nitrogen nucleophiles

One of PolySciTech’s latest product offerings is Akanocure stereotetrad lactones (https://akinainc.com/polyscitech/products/akanocure/index.php) for use as synthetic precursors. There are many potential reactions for these lactones which can result in a wide array of useful molecules. In this series of postings, we will highlight potential uses of these materials. These lactones can be ring-opened using secondary nitrogens as the nucleophilic agent. Previously, this reaction has been used to synthesize portions of Aplyronine A, a potent, chemotherapeutic marine macrolide. This research holds promise for enhanced synthesis of difficult-to-source chemotherapy agents. Read more: Hong, Wan Pyo, Mohammad N. Noshi, Ahmad El-Awa, and Philip L. Fuchs. “Synthesis of the C1–C20 and C15–C27 Segments of Aplyronine A.” Organic letters 13, no. 24 (2011): 6342-6345. http://pubs.acs.org/doi/abs/10.1021/ol2024746

“Abstract: The synthesis of C1–C20 and C15–C27 segments of Aplyronine A is described. Oxidative cleavage of cyclic vinyl sulfones has been used to prepare key fragments of Aplyronine A. Key precursors are united by Horner–Wadsworth–Emmons and Julia–Kociensky olefination for the respective elaboration of the C1–C20 and C15–C27 segments.”

Uses for Akanocure Stereotetrad Lactones 2b: lactone openings with primary nitrogen nucleophiles

One of PolySciTech’s latest product offerings is Akanocure stereotetrad lactones (https://akinainc.com/polyscitech/products/akanocure/index.php) for use as synthetic precursors. There are many potential reactions for these lactones which can result in a wide array of useful molecules. In this series of postings, we will highlight potential uses of these materials. One usage is opening the lactone ring utilizing primary nitrogens (amines). This method has been utilized to generate rhizopodin, a myxobacterial metabolite which is a potent actin-binding chemotherapeutic agent. This research holds promise for improved availability of effective chemotherapy agents. Read more: Dieckmann, Michael, Manuel Kretschmer, Pengfei Li, Sven Rudolph, Daniel Herkommer, and Dirk Menche. “Total synthesis of rhizopodin.” Angewandte Chemie International Edition 51, no. 23 (2012): 5667-5670. http://onlinelibrary.wiley.com/doi/10.1002/anie.201301978/full

“The total synthesis of the myxobacterial metabolite rhizopodin, a potent actin-binding anticancer agent, has been achieved. The modular synthesis utilizes a common C1–C22 monomeric unit to assemble the dimeric 38-membered macrodiolide core, which was elaborated by a bidirectional boron-mediated aldol reaction to install the characteristic side-chains. The final global deprotection was critically dependent on the correct choice of silyl protecting groups at C16/C16′.”

Uses for Akanocure Stereotetrad Lactones 2a: lactone openings with primary nitrogen nucleophiles

One of PolySciTech’s latest product offerings is Akanocure stereotetrad lactones (https://akinainc.com/polyscitech/products/akanocure/index.php) for use as synthetic precursors. There are many potential reactions for these lactones which can result in a wide array of useful molecules. In this series of postings, we will highlight potential uses of these materials. One usage is opening the lactone ring utilizing primary nitrogens (amines). For example, these can be utilized to generate aldonamides, a class of widely applicable precursors in and of themselves. You can read more about this application here: Metta-Magaña, Alejandro J., Reyna Reyes-Martínez, and Hugo Tlahuext. “Crystal structure and NMR spectroscopy of aldonamides derived from d-glycero-d-gulo-heptono-1, 4-lactone.” Carbohydrate research 342, no. 2 (2007): 243-253. http://www.sciencedirect.com/science/article/pii/S0008621506005325

“Abstract: We report the preparation of 12 aldonamides derived from d-glycero-d-gulo-heptono-1,4-lactone, their NMR characterization and study (13C, 1H, 15N NMR) in Me2SO-d6 solution. The evaluation of the coupling constants 3JH,H has shown that the sugar chain conformation in solution is all-trans for the studied amides. Because some amides crystallized, we discussed the crystal packing and found motifs. The conformation of the amides in the crystal structures displays two sickles at C2 and C3, with the exception of one that is all-trans. The bends cause the formation of the mean planes C1–C2–C3 and C3–C4–C5–C6–C7 with an average interplanar angle of 88°. We found three main kinds of crystal packing depending on the N-substituent; head-to-tail, bilayer and pseudo-hexagonal mode, all the three show hydrogen-bonding networks that stabilize the crystal lattice. Keywords: Aldonamides; Conformation; 15N NMR; Crystal packing; Hydrogen bonding”

Uses for Akanocure Stereotetrad Lactones 1b: lactone openings with oxygen nucleophiles

One of PolySciTech’s latest product offerings is Akanocure stereotetrad lactones (https://akinainc.com/polyscitech/products/akanocure/index.php) for use as synthetic precursors. There are many potential reactions for these lactones which can result in a wide array of useful molecules. In this series of postings, we will highlight potential uses of these materials. One of the uses is to open the lactone ring utilizing an oxygen nucleophile. This reaction has been successfully applied towards the generation of (+)-Neopeltolide, a promising cytostatic, anti-proliferative macrolide which has a broad range of activity against cancerous cells. The chemical was originally isolated from a deep-water sponges and is very difficult to source naturally in usable quantities. This research usage holds promise for commercial scale synthesis of chemotherapeutic reagents that are difficult to extract from natural resources. You can read more about this application here: Guinchard, Xavier, and Emmanuel Roulland. “Total synthesis of the antiproliferative macrolide (+)-neopeltolide.” Organic letters 11, no. 20 (2009): 4700-4703. http://pubs.acs.org/doi/abs/10.1021/ol902047z?journalCode=orlef7&quickLinkVolume=11&quickLinkPage=4700&selectedTab=citation&volume=11

“A concise total synthesis of the very promising antiproliferative macrolide (+)-neopeltolide (1) has been performed in 16 steps. The main steps of this approach are a RuII-catalyzed alkyne−enal coupling, a Pd0-catalyzed desulfurative cross-coupling, and a stereoselective InIII-catalyzed propargylation. Four stereogenic centers out of six have been set thanks to substrate-controlled diastereoselective reactions with minimal reliance on protecting groups.”

Uses for Akanocure Stereotetrad Lactones 1a: lactone openings with oxygen nucleophiles

One of PolySciTech’s latest product offerings is Akanocure stereotetrad lactones (https://akinainc.com/polyscite…/products/akanocure/index.php) for use as synthetic precursors. There are many potential reactions for these lactones which can result in a wide array of useful molecules. In this series of postings, we will highlight potential uses of these materials. One of the uses is to open the lactone ring utilizing an oxygen nucleophile. This synthetic route has previously been used to generate peloruside A, a non-taxoid-site microtubule-stabilizing agent which has promise for chemotherapeutic actions similar to that of paclitaxel. This research usage holds promise for commercial scale synthesis of chemotherapeutic reagents that are difficult to extract from natural resources. You can read more about this application here: Hoye, Thomas R., Junha Jeon, Lucas C. Kopel, Troy D. Ryba, Manomi A. Tennakoon, and Yini Wang. “Total Synthesis of Peloruside A through Kinetic Lactonization and Relay Ring‐Closing Metathesis Cyclization Reactions.” Angewandte Chemie International Edition 49, no. 35 (2010): 6151-6155. http://onlinelibrary.wiley.com/…/10.1002/anie.201002293/full
“Abstract: A convergent total synthesis of peloruside A (1) is described. The key strategic features are a diastereoselective lactonization to generate a C5–C9 valerolactone from the C2-symmetric ketone 3, and a relay ring-closing metathesis reaction to produce a dehydrovalerolactone 2. A new isomer of 1, the valerolactone isopeloruside A (iso-1), was identified. MOM=methoxymethyl.”

Stereotetrad lactone precursors from Akanocure Pharmaceuticals now available through Akina, Inc.

The PolySciTech division of Akina, Inc. (www.polyscitech.com) strives to provide unique and hard-to-find research reagents.  Thanks to a distribution arrangement with Akanocure Pharmacueticals, a Purdue University spin-off company which focuses on finding synthetic routes for hard-to-obtain nature-based pharmaceutical ingredients, we are now distributing stereospecific precursors for generation of polypriopionate medicines. You can see more details about these exciting materials here (https://akinainc.com/polyscitech/products/akanocure/index.php).  These chemicals represent an exciting class of novel therapeutic compounds within the polyketide family. You can learn more about this class of materials and their therapeutic potential in a recent review article: Koskinen, Ari MP, and Kaisa Karisalmi. “Polyketide stereotetrads in natural products.” Chemical Society Reviews 34, no. 8 (2005): 677-690. https://www.researchgate.net/profile/Ari_Koskinen/publication/7577323_Polyketide_Stereotetrads_in_Natural_Products/links/09e4150252cfc302d8000000.pdf

“Abstract: Natural products (or secondary metabolites) remain as the most important source for discovery of new and potential drug molecules. With high resolution data of their structures, and the advancement of synthesis possibilities, analysis of the natural products based on their specific structural features is valuable to those entering the field. In this tutorial review we attempt such an analysis indicating the salient features of the structural classes with examples of the synthesis of each one of them. As the particular class of natural products, we have chosen polyketides.”

PLCL from PolySciTech used as part of 3D bio-printing a live-cell laden urethra for tissue engineering application

Tissue engineering, the field or repairing damaged or missing bodily tissue, often utilizes cell-scaffolds to provide an appropriate environment for cellular growth and proliferation. Often these scaffolds are manufactured using conventional solvent casting, electrospinning or other polymer processing techniques. With recent advances in 3D printing techniques, this methodology has come to the forefront for manufacturing of tissue engineering scaffolds. Recently, researchers utilized PLCL from PolySciTech (www.polyscitech.com) (PolyVivo AP179) and used it along with an advanced 3D printing system at the Wake Forest Institute for Regenerative Medicine (WFIRM) to create a mechanically biomimetic and cell-laden urethra which showed success in a rabbit model. This research holds promise to provide for advanced 3D printed or bioprinted parts for tissue engineering applications. Read more: Zhang, Kaile, Qiang Fu, James Yoo, Xiangxian Chen, Prafulla Chandra, Xiumei Mo, Lujie Song, Anthony Atala, and Weixin Zhao. “3D bioprinting of urethra with PCL/PLCL blend and dual autologous cells in fibrin hydrogel: an in vitro evaluation of biomimetic mechanical property and cell growth environment.” Acta Biomaterialia (2016). http://www.sciencedirect.com/science/article/pii/S1742706116306778

“Abstract: Urethral stricture is a common condition seen after urethral injury. The currently available treatments are inadequate and there is a scarcity of substitute materials used for treatment of urethral stricture. The traditional tissue engineering of urethra involves scaffold design, fabrication and processing of multiple cell types. In this study, we have used 3D bio-printing technology to fabricate cell-laden urethra in vitro with different polymer types and structural characteristics. We hypothesized that use of PCL and PLCL polymers with a spiral scaffold design could mimic the structure and mechanical properties of natural urethra of rabbits, and cell-laden fibrin hydrogel could give a better microenvironment for cell growth. With using an integrated bioprinting system, tubular scaffold was formed with the biomaterials; meanwhile, urothelial cells (UCs) and smooth muscle cells (SMCs) were delivered evenly into inner and outer layers of the scaffold separately within the cell-laden hydrogel. The PCL/PLCL (50:50) spiral scaffold demonstrated mechanical properties equivalent to the native urethra in rabbit. Evaluation of the cell bioactivity in the bioprinted urethra revealed that UCs and SMCs maintained more than 80% viability even at 7 days after printing. Both cell types also showed active proliferation and maintained the specific biomarkers in the cell-laden hydrogel. These results provided a foundation for further studies in 3D bioprinting of urethral constructs that mimic the natural urethral tissue in mechanical properties and cell bioactivity, as well a possibility of using the bioprinted construct for in vivo study of urethral implantation in animal model. The 3D bioprinting is a new technique to replace traditional tissue engineering. The present study is the first demonstration that it is feasible to create a urethral construct. Two kinds of biomaterials were used and achieved mechanical properties equivalent to that of native rabbit urethra. Bladder epithelial cells and smooth muscle cells were loaded in hydrogel and maintained sufficient viability and proliferation in the hydrogel. The highly porous scaffold could mimic a natural urethral base-membrane, and facilitate contacts between the printed epithelial cells and smooth muscle cells on both sides of the scaffold. These results provided a strong foundation for future studies on 3D bioprinted urethra. Keywords: Urethra stricture; Urethra; Tissue engineering; 3D bioprinting; Regenerative medicine”

PLGA from PolySciTech used as part of macrophage-targeted protein delivery system

Despite the development of many protein-based, or biologic, medicines their application has been limited due to difficulty in administration. An attractive target for medicinal delivery is macrophage cells, immune cells which attack foreign materials and pathogens, as the action, or inaction, of these cells are involved in many diseases. Recently, researchers at Kangwon National University in Korea utilized PLGA from PolySciTech (www.polyscitech.com) to deliver protein-based drugs to macrophages. Acid ended PLGA from PolySciTech (PolyVivo AP081) was conjugated to dopamine to form a nanoparticle which targeted towards macrophage cells.  This particle was found to be able to deliver a model protein (albumin) to these cells with high uptake. This research holds promise for treating a wide variety of diseases ranging from inflammatory disease to cancers. Read more:  Lee, Song Yi, and Hyun-Jong Cho. “Dopamine-conjugated poly (lactic-co-glycolic acid) nanoparticles for protein delivery to macrophages.” Journal of Colloid and Interface Science (2016). http://www.sciencedirect.com/science/article/pii/S0021979716309559

“Abstract: Poly(lactic-co-glycolic acid)-dopamine (PLGA-D)-based nanoparticles (NPs) were developed for the delivery of protein to macrophages. PLGA-D was synthesized via amide bond formation between the –NH2 group of D and the –COOH group of PLGA. Bovine serum albumin (BSA, model protein) was encapsulated in PLGA NPs and PLGA-D NPs, which had an approximately 200 nm mean diameter, < 0.2 polydispersity index, and negative zeta potential value. There was no increment in the mean diameters of BSA-loaded NPs after 24 h of incubation in biological fluid-simulated media (i.e., aqueous buffer and serum media). The primary, secondary, and tertiary structures of BSA released from the NPs were studied by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDSPAGE), circular dichroism, and fluorescence spectrophotometry; the structural stability of BSA was preserved during its encapsulation in the NPs and release from the NPs. PLGA/BSA NPs and PLGA-D/BSA NPs did not induce serious cytotoxicity in RAW 264.7 cells (mouse macrophage cell line) in an established concentration range. In RAW 264.7 cells, the intracellular accumulation of PLGA-D NPs was 2-fold higher than that of PLGA NPs. All of these findings indicated that PLGA-D NPs are a promising system for delivering proteins to macrophages. Keywords: dopamine; macrophage; nanoparticles; PLGA; protein”

PLGA-PEG-COOH precursor from PolySciTech used as part of development of brain-cancer targeting nanoparticle

One attractive aspect for treatment for cancer is ‘theranostics.’ Theranostics represents a combination of ‘thera’py and diag’nostics.’ The goal for this is to both treat the cancer therapeutically as well as apply an agent to render it more detectable so as to assist in either surgical removal or monitoring of progress. Recently, researchers utilized the precursor PLGA-PEG-COOH from PolySciTech (www.polyscitech.com) (PolyVivo AI076) as part of developing an aptamer decorated nanoparticle. The nanoparticle contained both superparamagnetic iron oxide nanocrystals, an MRI contrast agent, and doxorubicin, a chemotherapeutic agent. The formed nanoparticles were found to have good uptake towards glioma cells indicating their potential for theranostic applications towards brain cancer. This research holds promise for improved therapy of brain cancer. Read more: Mosafer, Jafar, Manouchehr Teymouri, Khalil Abnous, Mohsen Tafaghodi, and Mohammad Ramezani. “Study and evaluation of nucleolin-targeted delivery of magnetic PLGA-PEG nanospheres loaded with doxorubicin to C6 glioma cells compared with low nucleolin-expressing L929 cells.” Materials Science and Engineering: C (2016). http://www.sciencedirect.com/science/article/pii/S0928493116322068

“Highlights: Dox-containing PLGA-nanoparticle improves cancerous cytotoxicity of free Dox. Anti-nucleolin aptamer-nanoparticle leads to targeted cell delivery of drug. SPION containing PLGA-nanoparticle is apt for imaging purposes of tumors. PLGA releases doxorubicin inside cells, not outside the cells. PLGA could lead to improved drug retention in serum. Abstract: Magnetic nanoparticulate systems based on polymeric materials such as poly (lactic-co-glycolic acid) (PLGA 1) are being studied for their potential applications in targeted therapy and imaging of malignant tumors. In the current study, superparamagnetic iron oxide nanocrystals (SPIONs2) and doxorubicin (Dox3) were entrapped in the PLGA-based nanoparticles via a modified multiple emulsion solvent evaporation method. Furthermore, SPIO/Dox-NPs4 were conjugated to anti-nucleolin AS1411 aptamer (Apt5) and their targeting ability was investigated in high nucleolin-expressing C6 glioma cells compared to low nucleolin-expressing L929 cells. The NPs exhibited a narrow size distribution with mean diameter of ~ 170 nm and an appropriate SPION content (~ 18% of total polymer weight) with a sufficient saturation magnetization value of 5.9 emu/g which is suitable for imaging objectives. They manifested an increased Dox release at pH 5.5 compared to pH 7.4, with initial burst release (within 24 h) followed by sustained release of Dox for 36 days. The Apt conjugation to NPs enhanced cellular uptake of Dox in C6 glioma cells compared to L929 cells. Similarly, the Apt-NPs increased the cytotoxicity effect of Dox compared with NPs and Dox solution (f-Dox) alone. In conclusion, the Apt-NPs were found to be a promising delivery system for therapeutic and diagnostic purposes. Keywords: SPION; Doxorubicin; Glioma cell; Nucleolin; PLGA; Aptamer”