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Bradley S. Moore - One of the best experts on this subject based on the ideXlab platform.
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Coupled Biosynthesis of Volatiles and Salinosporamide A in Salinispora tropica
ChemBioChem, 2016Co-Authors: Ulrike Groenhagen, Bradley S. Moore, Ana Ligia Leandrini De Oliveira, Elisha N. Fielding, Stefan SchulzAbstract:Terrestrial bacteria, especially actinomycetes, are known to be prolific producers of volatile compounds. We show here that bacteria from ocean sediments can also release complex bouquets of volatiles. The actinomycete Salinispora tropica produces cyclohexenyl compounds not previously known in nature, such as methyl cyclohex-2-ene-1-carboxylate (9), methyl 2-(cyclohex-2-en-1-yl)acetate (10), methyl (E/Z)-2-(cyclohex-2-en-1-ylidene)acetate (11/12), and related alcohols 8 and 13. These compounds were identified by GC/MS and confirmed by synthesis. In addition, rare spiroacetals, aromatic compounds, short-chain acids and esters, alcohols, and various cyclic compounds were produced by the bacteria. The biosynthesis of the cyclohexenyl compounds is closely coupled to that of cyclohexenylalanine (4), a building block of Salinosporamide A, a proteasome inhibitor produced by S. tropica. Analysis of S. tropica strains that harbor knockouts of the Salinosporamide biosynthetic genes salX and salD, coupled with feeding experiments, revealed that 3-(cyclohex-2-en-1-yl)-2-oxopropanoic acid (60) and 3-(cyclohex-2-en-1-ylidene)-2-oxopropanoic acid (isomers 61 and 62) are important intermediates in the biosynthesis of Salinosporamide A, 4, and 8-13.
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Antileukemic activity and mechanism of drug resistance to the marine Salinispora tropica proteasome inhibitor Salinosporamide A (Marizomib).
Molecular Pharmacology, 2014Co-Authors: Denise Niewerth, Bradley S. Moore, Gerrit Jansen, Lesley F. V. Riethoff, Johan Van Meerloo, Andrew J. Kale, Yehuda G. Assaraf, Janet L. Anderl, Sonja Zweegman, Gertjan J. L. KaspersAbstract:Salinosporamide A (NPI-0052, marizomib) is a naturally occurring proteasome inhibitor derived from the marine actinobacterium Salinispora tropica, and represents a promising clinical agent in the treatment of hematologic malignancies. Recently, these actinobacteria were shown to harbor self-resistance properties to Salinosporamide A by expressing redundant catalytically active mutants of the 20S proteasome β-subunit, reminiscent of PSMB5 mutations identified in cancer cells with acquired resistance to the founding proteasome inhibitor bortezomib (BTZ). Here, we assessed the growth inhibitory potential of Salinosporamide A in human acute lymphocytic leukemia CCRF-CEM cells, and its 10-fold (CEM/BTZ7) and 123-fold (CEM/BTZ200) bortezomib-resistant sublines harboring PSMB5 mutations. Parental cells displayed sensitivity to Salinosporamide A (IC50 = 5.1 nM), whereas their bortezomib-resistant sublines were 9- and 17-fold cross-resistant to Salinosporamide A, respectively. Notably, combination experiments of Salinosporamide A and bortezomib showed synergistic activity in CEM/BTZ200 cells. CEM cells gradually exposed to 20 nM Salinosporamide A (CEM/S20) displayed stable 5-fold acquired resistance to Salinosporamide A and were 3-fold cross-resistant to bortezomib. Consistent with the acquisition of a PSMB5 point mutation (M45V) in CEM/S20 cells, Salinosporamide A displayed a markedly impaired capacity to inhibit β5-associated catalytic activity. Last, compared with parental CEM cells, CEM/S20 cells exhibited up to 2.5-fold upregulation of constitutive proteasome subunits, while retaining unaltered immunoproteasome subunit expression. In conclusion, Salinosporamide A displayed potent antileukemic activity against bortezomib-resistant leukemia cells. β-Subunit point mutations as a common feature of acquired resistance to Salinosporamide A and bortezomib in hematologic cells and S. tropica suggest an evolutionarily conserved mechanism of resistance to proteasome inhibitors.
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Coupling of sterically hindered aldehyde with fluorinated synthons: Stereoselective synthesis of fluorinated analogues of Salinosporamide A
Journal of Fluorine Chemistry, 2012Co-Authors: Zeng-hao Chen, Bradley S. Moore, Andrew J. Kale, Bing-lin Wang, Ruowen Wang, Feng-ling QingAbstract:Salinosporamide A is an irreversible inhibitor of the beta-subunits of the 20S proteasome. Its C-5 cyclohexenyl moiety is the key to its affinity and potency as an anticancer agent. Here we describe the synthesis of C-5 difluoromethylated and trifluoromethylated analogues of Salinosporamide A and their biological evaluation as proteasome inhibitors against purified yeast 20S proteasome. The synthetic strategy featured the stereoselective coupling reaction of sterically hindered aldehyde 3 with fluorinated organolithium reagents. (C) 2012 Elsevier B.V. All rights reserved.
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Molecular Mechanisms of Acquired Proteasome Inhibitor Resistance
2012Co-Authors: Andrew J. Kale, Bradley S. MooreAbstract:The development of proteasome inhibitors (PIs) has transformed the treatment of multiple myeloma and mantle cell lymphoma. To date, two PIs have been FDA approved, the boronate peptide bortezomib and, most recently, the epoxyketone peptide carfilzomib. However, intrinsic and acquired resistance to PIs, for which the underlying mechanisms are poorly understood, may limit their efficacy. In this Perspective, we discuss recent advances in the molecular understanding of PI resistance through acquired bortezomib resistance in human cell lines and evolved Salinosporamide A (marizomib) resistance in bacteria. Resistance mechanisms discussed include the up-regulation of proteasome subunits and mutations of the catalytic β-subunits. Additionally, we explore potential strategies to overcome PI resistance
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Bacterial self-resistance to the natural proteasome inhibitor Salinosporamide A.
ACS Chemical Biology, 2011Co-Authors: Andrew J. Kale, Anna Lechner, Ryan P. Mcglinchey, Bradley S. MooreAbstract:Proteasome inhibitors have recently emerged as a therapeutic strategy in cancer chemotherapy, but susceptibility to drug resistance limits their efficacy. The marine actinobacterium Salinispora tropica produces Salinosporamide A (NPI-0052, marizomib), a potent proteasome inhibitor and promising clinical agent in the treatment of multiple myeloma. Actinobacteria also possess 20S proteasome machinery, raising the question of self-resistance. We identified a redundant proteasome β-subunit, SalI, encoded within the Salinosporamide biosynthetic gene cluster and biochemically characterized the SalI proteasome complex. The SalI β-subunit has an altered substrate specificity profile, 30-fold resistance to Salinosporamide A, and cross-resistance to the FDA-approved proteasome inhibitor bortezomib. An A49V mutation in SalI correlates to clinical bortezomib resistance from a human proteasome β5-subunit A49T mutation, suggesting that intrinsic resistance to natural proteasome inhibitors may predict clinical outcomes.
William Fenical - One of the best experts on this subject based on the ideXlab platform.
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Marine Actinomycetes: A New Source of Compounds against the Human Malaria Parasite
2013Co-Authors: Jacques Prudhomme, Eric Mcdaniel, Nadia Ponts, Paul Jensen, William Fenical, Stéphane Bertani, Karine Le RochAbstract:Background: Malaria continues to be a devastating parasitic disease that causes the death of 2 million individuals annually. The increase in multi-drug resistance together with the absence of an efficient vaccine hastens the need for speedy and comprehensive antimalarial drug discovery and development. Throughout history, traditional herbal remedies or natural products have been a reliable source of antimalarial agents, e.g. quinine and artemisinin. Today, one emerging source of small molecule drug leads is the world’s oceans. Included among the source of marine natural products are marine microorganisms such as the recently described actinomycete. Members of the genus Salinispora have yielded a wealth of new secondary metabolites including Salinosporamide A, a molecule currently advancing through clinical trials as an anticancer agent. Because of the biological activity of metabolites being isolated from marine microorganisms, our group became interested in exploring the potential efficacy of these compounds against the malaria parasite. Methods: We screened 80 bacterial crude extracts for their activity against malaria growth. We established that the pure compound, Salinosporamide A, produced by the marine actinomycete, Salinispora tropica, shows strong inhibitory activity against the erythrocytic stages of the parasite cycle. Biochemical experiments support the likely inhibition of the parasite 20S proteasome. Crystal structure modeling of Salinosporamide A and the parasite catalytic 20S subunit further confirm this hypothesis. Ultimately we showed that Salinosporamide A protected mice against deadly malaria infection whe
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Effect of Salinosporamide A on parasite morphology.
2013Co-Authors: Jacques Prudhomme, Eric Mcdaniel, Nadia Ponts, Paul Jensen, William Fenical, Stéphane Bertani, Karine Le RochAbstract:Parasites were synchronized twice using sorbitol method. Salinosporamide A was added at the IC80 to ring (A), trophozoite (B) or schizont (C) stage. Morphological changes were observed every 6 or 12 hours by microscopic examination.
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Inhibition effect of Salinosporamide A on chloroquine resistant P. falciparum strain FCB.
2013Co-Authors: Jacques Prudhomme, Eric Mcdaniel, Nadia Ponts, Paul Jensen, William Fenical, Stéphane Bertani, Karine Le RochAbstract:IC50 values of parasite treated with the drug were determined using the SYBR Green assay. Each value in the curve is the average of 2 different experiments±standard deviation. Salinosporamide A inhibited the proliferation of the FCB strain suggesting that the compound is equally active against drug resistant parasites. IC50 values with Salinosporamide A were 11.4 nM±1.9 for 3D7 (R = 0.9887) and 19.6 nM±1.4 for FCB (R = 0.9990). Chloroquine IC50 values were 2.3 nM±0.15 (R = 0.9996) and 64.1 nM±4.7 (R = 0.9964) for 3D7 and FCB respectively.
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Western blot analysis of parasite proteins using anti-ubiquitin antibodies.
2013Co-Authors: Jacques Prudhomme, Eric Mcdaniel, Nadia Ponts, Paul Jensen, William Fenical, Stéphane Bertani, Karine Le RochAbstract:Synchronized 3D7 parasite cultures were treated with the IC80 value of Salinosporamide A (line 2) or MG-132 (Line 3). Following parasite treatment with the drug, parasite extracts were analyzed for the presence of ubiquitin-conjugates. Ubiquitinated proteins accumulate in the drugs treated when compared to the untreated cultures.
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Figure 5
2013Co-Authors: Jacques Prudhomme, Eric Mcdaniel, Nadia Ponts, Paul Jensen, William Fenical, Stéphane Bertani, Karine Le RochAbstract:(A) Sequence alignment of the catalytic domain of the β5 subunit 20 S proteasome from yeast, human and Plasmodium obtained with the ClustalW program. (B) Crystal structure of Salinosporamide A interacting with the yeast 20S proteasome. Tyr168 is shown in orange to indicate the site of the Y168G mutation in P. falciparum.
Barbara C. M. Potts - One of the best experts on this subject based on the ideXlab platform.
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Trypanocidal activity of β-lactone-γ-lactam proteasome inhibitors.
Planta Medica, 2012Co-Authors: Dietmar Steverding, Barbara C. M. Potts, Xia Wang, Michael A PalladinoAbstract:Four beta-lactone-gamma-lactam proteasome inhibitors of natural origin were tested for their trypanocidal activities IN VITRO using culture-adapted bloodstream forms of TRYPANOSOMA BRUCEI. All four compounds displayed activities in the nanomolar range. The most trypanocidal compounds with 50?% growth inhibition (GI (50)) values of around 3 nM were the bromine and iodine analogues of Salinosporamide A, a potent proteasome inhibitor produced by the marine actinomycete SALINISPORA TROPICA. In general, trypanosomes were more susceptible to the compounds than were human HL-60 cells. The data support the potential of beta-lactone-gamma-lactam proteasome inhibitors for rational anti-trypanosomal drug development.
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Concise formal synthesis of (-)-Salinosporamide A (marizomib) using a regio- and stereoselective epoxidation and reductive oxirane ring-opening strategy.
The Journal of Organic Chemistry, 2010Co-Authors: Taotao Ling, Barbara C. M. Potts, Venkat R. MacherlaAbstract:Expedient access to a highly functionalized 2-pyrrolidinone (8), the gamma-lactam core of 20S proteasome inhibitor (-)-Salinosporamide A (marizomib; NPI-0052; 1), using a regio- and stereoselective epoxide formation/reductive oxirane ring-opening strategy is presented. Notably, the sequential construction of the C-4, C-3, and C-2 stereocenters of 1 in a completely stereocontrolled fashion is a key feature of streamlining the synthesis of intermediate 12. A related strategy is also discussed.
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Generating a Generation of Proteasome Inhibitors: From Microbial Fermentation to Total Synthesis of Salinosporamide A (Marizomib) and Other Salinosporamides
Marine Drugs, 2010Co-Authors: Barbara C. M. Potts, Kin Sing LamAbstract:The Salinosporamides are potent proteasome inhibitors among which the parent marine-derived natural product Salinosporamide A (marizomib; NPI-0052; 1) is currently in clinical trials for the treatment of various cancers. Methods to generate this class of compounds include fermentation and natural products chemistry, precursor-directed biosynthesis, mutasynthesis, semi-synthesis, and total synthesis. The end products range from biochemical tools for probing mechanism of action to clinical trials materials; in turn, the considerable efforts to produce the target molecules have expanded the technologies used to generate them. Here, the full complement of methods is reviewed, reflecting remarkable contributions from scientists of various disciplines over a period of 7 years since the first publication of the structure of 1.
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stereoselective enzymatic reduction of keto Salinosporamide to Salinosporamide a npi 0052
Tetrahedron Letters, 2007Co-Authors: Rama Rao Manam, Venkat R. Macherla, Barbara C. M. PottsAbstract:Salinosporamide A (NPI-0052, 1), a highly potent 20S proteasome inhibitor, has been prepared from its ketone precursor (2) by asymmetric enzymatic reduction. The yields are quantitative with complete stereoselective conversion to the desired product, with no evidence for the undesired diastereomer. This process should lead to new synthetic strategies for the total synthesis of 1.
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Enantioselective Total Synthesis of (-)-Salinosporamide A (NPI-0052)
Organic Letters, 2007Co-Authors: Taotao Ling, Venkat R. Macherla, Rama Rao Manam, Katherine A. Mcarthur, Barbara C. M. PottsAbstract:A novel enantioselective total synthesis of 20S proteasome inhibitor Salinosporamide A (NPI-0052; 1) is presented. Key features include intramolecular aldol cyclization of 6 to simultaneously generate the three chiral centers of advanced intermediate 5, cyclohexene ring addition using B-2-cyclohexen-1-yl-9-BBN, and inversion of the C-5 stereocenter by oxidation followed by enantioselective enzymatic reduction.
Alessandra S. Eustáquio - One of the best experts on this subject based on the ideXlab platform.
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Selective Overproduction of the Proteasome Inhibitor Salinosporamide A via Precursor Pathway Regulation
Chemistry & Biology, 2011Co-Authors: Anna Lechner, Tobias A M Gulder, Alessandra S. Eustáquio, Mathias Hafner, Bradley S. MooreAbstract:Summary The chlorinated natural product Salinosporamide A is a potent 20S proteasome inhibitor currently in clinical trials as an anticancer agent. To deepen our understanding of Salinosporamide biosynthesis, we investigated the function of a LuxR-type pathway-specific regulatory gene, salR2, and observed a selective effect on the production of Salinosporamide A over its less active aliphatic analogs. SalR2 specifically activates genes involved in the biosynthesis of the halogenated precursor chloroethylmalonyl-CoA, which is a dedicated precursor of Salinosporamide A. Specifically, SalR2 activates transcription of two divergent operons—one of which contains the unique S -adenosyl-L-methionine-dependent chlorinase encoding gene salL . By applying this knowledge to rational engineering, we were able to selectively double Salinosporamide A production. This study exemplifies the specialized regulation of a polyketide precursor pathway and its application to the selective overproduction of a specific natural product congener.
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The discovery of Salinosporamide K from the marine bacterium "Salinispora pacifica" by genome mining gives insight into pathway evolution.
ChemBioChem, 2010Co-Authors: Alessandra S. Eustáquio, Paul R. Jensen, William Fenical, Anna Lechner, Sang-jip Nam, Kevin Penn, Micheal C. Wilson, Bradley S. MooreAbstract:The γ-lactam-β-lactone natural product Salinosporamide A (1) is a potent proteasome inhibitor produced by the marine bacterium Salinispora tropica.[1,2] This chlorinated anticancer agent dominates a family of natural structural analogues that primarily differ at the C-2 substituent.[3] In the case of 1, the C-2 chloroethyl group is a key functional group that enables the molecule to irreversibly bind to the 20S proteasome.[4] All γ-lactam-β-lactone natural products, including the Salinosporamides (1–4), the cinnabaramides (5), and omuralide (6), share the initial reaction with the proteasome in which the N-terminal threo-nine residue of the catalytic β-subunit attacks the β-lactone group of the inhibitor to form an ester linkage.[3] While this covalent proteasome–inhibitor complex is susceptible to water hydrolysis, a subsequent reaction of the β-lactone-derived C-3 hydroxyl group with a C-2 side-chain leaving group such as in 1 yields a tetrahydrofuran adduct that is stable to hydrolysis.[4] Due to the mechanistic importance of the Salinosporamide C-2 substituent, biosynthetic studies in S. tropica explored the origins of this small compound library to reveal that the Salinosporamides are atypical products of a hybrid polyketide synthase–nonribosomal peptide synthetase (PKS–NRPS).[5,6] By accommodating different PKS building blocks such as chloroethyl-, methyl-, ethyl-, and propyl-malonyl-CoA, Salinosporamides A(1), D (2), B (3) and E (4), respectively, are biosynthesized.[6,7] This understanding provided the logic to engineer the unnatural derivative fluoroSalinosporamide[8,9] (7) as well as the molecular basis to explore new genome sequences for the discovery of novel Salinosporamide derivatives. Herein we report the genome-inspired discovery and characterization of Salinosporamide K (8) from a new source, “Salinispora pacifica” strain CNT-133, that provides insight into the evolution of the Salinosporamide biosynthetic pathway. From the three proposed Salinispora species, S. tropica and “S. pacifica” are more closely related to each other than each is to S. arenicola.[10]
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biosynthesis of Salinosporamides from α β unsaturated fatty acids implications for extending polyketide synthase diversity
Journal of the American Chemical Society, 2009Co-Authors: Christopher Hazzard, Alessandra S. Eustáquio, Kevin A Reynolds, Bradley S. MooreAbstract:A new series of coenzyme A-tethered polyketide synthase extender units were discovered in relation to the biosynthesis of the Salinosporamide family of anticancer agents from the marine bacterium Salinispora tropica. In vivo and in vitro experiments revealed that the crotonyl-CoA reductase/carboxylase SalG has broad substrate tolerance toward 2-alkenyl-CoAs that give rise to the Salinosporamide C-2 substitution pattern.
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Biosynthesis of the Salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S-adenosyl-l-methionine
Proceedings of the National Academy of Sciences, 2009Co-Authors: Alessandra S. Eustáquio, Anna Lechner, Andrew J. Kale, Ryan P. Mcglinchey, Yuan Liu, Christopher Hazzard, Laura L. Beer, Galina Florova, Mamoun M. Alhamadsheh, Yoshihisa KobayashiAbstract:Polyketides are among the major classes of bioactive natural products used to treat microbial infections, cancer, and other diseases. Here we describe a pathway to chloroethylmalonyl-CoA as a polyketide synthase building block in the biosynthesis of Salinosporamide A, a marine microbial metabolite whose chlorine atom is crucial for potent proteasome inhibition and anticancer activity. S-adenosyl-l-methionine (SAM) is converted to 5′-chloro-5′-deoxyadenosine (5′-ClDA) in a reaction catalyzed by a SAM-dependent chlorinase as previously reported. By using a combination of gene deletions, biochemical analyses, and chemical complementation experiments with putative intermediates, we now provide evidence that 5′-ClDA is converted to chloroethylmalonyl-CoA in a 7-step route via the penultimate intermediate 4-chlorocrotonyl-CoA. Because halogenation often increases the bioactivity of drugs, the availability of a halogenated polyketide building block may be useful in molecular engineering approaches toward polyketide scaffolds.
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discovery and characterization of a marine bacterial sam dependent chlorinase
Nature Chemical Biology, 2008Co-Authors: Alessandra S. Eustáquio, Bradley S. Moore, Florence Pojer, Joseph P NoelAbstract:Halogen atom incorporation into a scaffold of bioactive compounds often amplifies biological activity, as is the case for the anticancer agent Salinosporamide A (1), a chlorinated natural product from the marine bacterium Salinispora tropica. Significant effort in understanding enzymatic chlorination shows that oxidative routes predominate to form reactive electrophilic or radical chlorine species. Here we report the genetic, biochemical and structural characterization of the chlorinase SalL, which halogenates S-adenosyl-L-methionine (2) with chloride to generate 5′-chloro-5′-deoxyadenosine (3) and L-methionine (4) in a rarely observed nucleophilic substitution strategy analogous to that of Streptomyces cattleya fluorinase. Further metabolic tailoring produces a halogenated polyketide synthase substrate specific for Salinosporamide A biosynthesis. SalL also accepts bromide and iodide as substrates, but not fluoride. High-resolution crystal structures of SalL and active site mutants complexed with substrates and products support the SN2 nucleophilic substitution mechanism and further illuminate halide specificity in this newly discovered halogenase family.
Daniel Romo - One of the best experts on this subject based on the ideXlab platform.
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(−)-HomoSalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study
MDPI AG, 2018Co-Authors: Michael Groll, Henry Nguyen, Sreekumar Vellalath, Daniel RomoAbstract:Upon acylation of the proteasome by the β-lactone inhibitor Salinosporamide A (SalA), tetrahydrofuran formation occurs by intramolecular alkylation of the incipient alkoxide onto the choroethyl sidechain and irreversibly blocks the active site. Our previously described synthetic approach to SalA, utilizing a bioinspired, late-stage, aldol-β-lactonization strategy to construct the bicyclic β-lactone core, enabled synthesis of (–)-homoSalinosporamide A (homoSalA). This homolog was targeted to determine whether an intramolecular tetrahydropyran is formed in a similar manner to SalA. Herein, we report the X-ray structure of the yeast 20S proteasome:homoSalA-complex which reveals that tetrahydropyran ring formation does not occur despite comparable potency at the chymotrypsin-like active site in a luminogenic enzyme assay. Thus, the natural product derivative homoSalA blocks the proteasome by a covalent reversible mode of action, opening the door for further fine-tuning of proteasome inhibition
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bioinspired total synthesis and human proteasome inhibitory activity of Salinosporamide a homoSalinosporamide a and derivatives obtained via organonucleophile promoted bis cyclizations
Journal of Organic Chemistry, 2011Co-Authors: Henry Nguyen, Tatiana Gladysheva, Trisha Fremgen, Daniel RomoAbstract:A full account of concise, enantioselective syntheses of the anticancer agent (−)-Salinosporamide A and derivatives, including (−)-homoSalinosporamide, that was inspired by biosynthetic considerations is described. The brevity of the synthetic strategy stems from a key bis-cyclization of a β-keto tertiary amide, which retains optical purity enabled by A1,3-strain rendering slow epimerization relative to the rate of bis-cyclization. Optimization studies of the key bis-cyclization, enabled through byproduct isolation and characterization, are described that ultimately allowed for a gram scale synthesis of a versatile bicyclic core structure with a high degree of stereoretention. An optimized procedure for zincate generation by the method of Knochel, generally useful for the synthesis of salino A derivatives, led to dramatic improvements in side-chain attachment and a novel diastereomer of salino A. The versatility of the described strategy is demonstrated by the synthesis of designed derivatives including (...
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a 1 3 strain enabled retention of chirality during bis cyclization of β ketoamides total synthesis of Salinosporamide a and homoSalinosporamide a
ChemInform, 2010Co-Authors: Henry Nguyen, Daniel RomoAbstract:(-)-Salinosporamide A (IVa) and (-)-homoSalinosporamide A (IVb) are prepared via a diastereoselective bis-cyclization of β-keto tertiary amide of type (II) as key step.
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a1 3 strain enabled retention of chirality during bis cyclization of β ketoamides total synthesis of Salinosporamide a and homoSalinosporamide a
Chemical Communications, 2010Co-Authors: Henry Nguyen, Daniel RomoAbstract:A concise, enantioselective synthesis of the Phase I anticancer agent, (−)-Salinosporamide A, is described. The brevity of the described strategy stems from a key bis-cyclization of a β-keto tertiary amide, accomplished on gram scale, which retains optical purity enabled by A1,3-strain rendering epimerization slow relative to the rate of bis-cyclization. The versatility of the strategy for derivative synthesis is demonstrated by the synthesis of (−)-homoSalinosporamide A.
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concise total synthesis of Salinosporamide a cinnabaramide a and derivatives via a bis cyclization process implications for a biosynthetic pathway
Organic Letters, 2007Co-Authors: Henry Nguyen, Daniel RomoAbstract:4-Alkylidene-β-lactones (hetero ketene dimers) and α-amino acids are useful precursors for total syntheses of the β-lactone-containing proteasome inhibitors Salinosporamide A, cinnabaramide A, and derivatives. A key step is a nucleophile-promoted, bis-cyclization of keto acids that simultaneously generates the γ-lactam and β-lactone of these natural products. This reaction sequence may have implications for the biosynthesis of these natural products.
