- RITA Mimics: Synthesis and Mechanistic Evaluation of Asymmetric Linked Trithiazoles
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The established cytotoxic agent RITA contains a thiophene-furan-thiophene backbone and two terminal alcohol groups. Herein we investigate the effect of using thiazoles as the backbone in RITA-like molecules and modifying the terminal groups of these trithiazoles, thereby generating 41 unique structures. Incorporating side chains with varied steric bulk allowed us to investigate how size and a stereocenter impacted biological activity. Subjecting compounds to growth inhibition assays on HCT-116 cells showed that the most potent compounds 7d, 7e, and 7h had GI50 values of 4.4, 4.4, and 3.4 μM, respectively, versus RITA (GI50 of 800 nM). Analysis of these compounds in apoptosis assays proved that 7d, 7e, and 7h were as effective as RITA at inducing apoptosis. Evaluating the impact of 7h on proteins targeted by RITA (p53, c-Myc, and Mcl-1) indicated that it acts via a different mechanism of action to that of RITA. RITA suppressed Mcl-1 protein via p53, whereas compound 7h suppressed Mcl-1 expression via an alternative mechanism independent of p53.
- Pietkiewicz, Adrian L.,Zhang, Yuqi,Rahimi, Marwa N.,Stramandinoli, Michael,Teusner, Matthew,McAlpine, Shelli R.
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supporting information
p. 401 - 406
(2017/04/21)
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- Design, synthesis and anticancer mechanistic studies of linked azoles
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Herein we report the synthesis and biological activity evaluation of 2,4 linked azole-containing molecules. A total of 13 linked thiazole- and oxazole-containing compounds were synthesized in good yields. Cytotoxicity evaluation of those compounds showed
- Islam, Md. Amirul,Zhang, Yuqi,Wang, Yao,McAlpine, Shelli R.
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supporting information
p. 300 - 305
(2015/03/30)
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- Chemoenzymatic Synthesis of Thiazolyl Peptide Natural Products Featuring an Enzyme-Catalyzed Formal [4 + 2] Cycloaddition
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Thiocillins from Bacillus cereus ATCC 14579 are members of the well-known thiazolyl peptide class of natural product antibiotics, the biosynthesis of which has recently been shown to proceed via post-translational modification of ribosomally encoded precursor peptides. It has long been hypothesized that the final step of thiazolyl peptide biosynthesis involves a formal [4 + 2] cycloaddition between two dehydroalanines, a unique transformation that had eluded enzymatic characterization. Here we demonstrate that TclM, a single enzyme from the thiocillin biosynthetic pathway, catalyzes this transformation. To facilitate characterization of this new class of enzyme, we have developed a combined chemical and biological route to the complex peptide substrate, relying on chemical synthesis of a modified C-terminal fragment and coupling to a 38-residue leader peptide by means of native chemical ligation (NCL). This strategy, combined with active enzyme, provides a new chemoenzymatic route to this promising class of antibiotics.
- Wever, Walter J.,Bogart, Jonathan W.,Baccile, Joshua A.,Chan, Andrew N.,Schroeder, Frank C.,Bowers, Albert A.
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supporting information
p. 3494 - 3497
(2015/03/30)
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- Sanguinamide B analogs: Identification of active macrocyclic structures
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We report the synthesis of three new sanguinamide B (San B) analogs. We substituted in amino acids along the San B backbone with an N-Me, glycine, or an aromatic moiety (Phe or d-Phe) generating twelve derivatives in total. Testing in HCT-116 colon cancer
- Wahyudi, Hendra,Tantisantisom, Worawan,McAlpine, Shelli R.
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supporting information
p. 2389 - 2393
(2014/05/06)
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- Synthesis of o -me ulongamide b and o -me ulongamide c, natural modified cyclodepsipeptides
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Synthesis of O-Me ulongamide B and O-Me ulongamide C, modified natural cyclodepsipeptides, was achieved by a convergent route. The respective dipeptides and tridepsipeptides were coupled, obtaining linear depsipentapeptides, which were then deprotected and cyclized. These compounds were tested against three different types of human carcinoma cells and showed only moderate activity.
- Alvarado, Cuauhtémoc,Hernández, Gerardo,Díaz, Eduardo,Soano, José D.,Vilchis-Reyes, Miguel A.,Martínez-Urbina, Miguel A.,Guzmán, Angel
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p. 993 - 1006
(2013/03/13)
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- Mechanistic studies of sanguinamide B derivatives: A unique inhibitor of eukaryotic ribosomes
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Described are mechanistic studies of two Sanguinamide B (San B) derivatives. These compounds were identified as eukaryotic ribosomal inhibitors. Two biotinylated San B derivatives were synthesized and used to capture protein targets in a pull-down assay.
- Tantisantisom, Worawan,Ramsey, Deborah M.,McAlpine, Shelli R.
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supporting information
p. 4638 - 4641
(2013/10/08)
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- Total synthesis of trans, trans- Sanguinamide B and conformational isomers
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The first total synthesis of Sanguinamide B is reported, prepared via an efficient synthetic strategy. The natural product, trans,trans-Sanguinamide B (1), was generated in a thermodynamic ratio with trans,cis-Sanguinamide B (2) and cis,cis-Sanguinamide B
- Singh, Erinprit K.,Ramsey, Deborah M.,McAlpine, Shelli R.
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supporting information; experimental part
p. 1198 - 1201
(2012/05/04)
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- HIV protease inhibiting compounds
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A compound of the formula is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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Page/Page column 112
(2011/01/12)
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- SUBSTITUTED HYDROXAMIC ACIDS AND USES THEREOF
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This invention provides compounds of formula (I): wherein X1, X2, X3, R2, R4b, R1, and G have values as described in the specification, useful as inhibitors of HDAC6. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of proliferative, inflammatory, infectious, neurological or cardiovascular diseases or disorders.
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Page/Page column 70
(2011/09/20)
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- Synthesis of the thiazole-thiazoline fragment of largazole analogues
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The thiazole - thiazoline fragment of the marine natural product largazole, a potent histone deacetylase 1 inhibitor, has been synthesized in five steps. The methodology provides rapid access to thiazole-4-carbonitrile, thiazole-4-carbimidate, thiazole -
- Diness, Frederik,Nielsen, Daniel S.,Fairlie, David P.
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experimental part
p. 9845 - 9851
(2012/01/02)
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- Total synthesis of ulongamide A, a cyclic depsipeptide isolated from marine cyanobacteria Lyngbya sp.
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A total synthesis of ulongamide A (1), a cytotoxic natural cyclic depsipeptide, was achieved by a convergent route involving coupling of the fragments 7 and 8 to the pentapeptide 24, and subsequent cyclization thereof after prior removal of the t-Boc protecting groups.
- Alvarado, Cuauhtémoc,Díaz, Eduardo,Guzmán, ángel
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p. 603 - 607
(2007/10/03)
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- Enantioswitchable catalysts for the asymmetric transfer hydrogenation of aryl alkyl ketones
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(Chemical Equation Presented) A subtle change in the ligand structure, replacing the carbonyl oxygen with sulfur in simple α-amino acid amides, resulted in a dramatic activity and selectivity improvement in the rhodium- or ruthenium-catalyzed reduction of ketones under hydrogen transfer conditions. In addition, in most cases, a switch of the product's absolute configuration was observed on going from amides to the corresponding thioamides. Under optimized conditions, we obtained the secondary alcohol products in high yield and enantioselectivity (up to 97% ee) using only 0.25 mol % catalyst loading.
- Zaitsev, Alexey B.,Adolfsson, Hans
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p. 5129 - 5132
(2007/10/03)
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- HIV protease inhibiting compounds
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A compound of the formula is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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Page/Page column 124
(2010/02/12)
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- Synthesis of Dolastatin I, a cytotoxic cyclic hexapeptide from the sea hare Dolabella auricularia
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Dolastatin I, a cytotoxic cyclic hexapeptide isolated from the Japanese sea hare Dolabella auricularia, was enantioselectively synthesized, which confirmed its stereostructure.
- Kigoshi, Hideo,Yamada, Shiho
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p. 12301 - 12308
(2007/10/03)
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- Practical Synthesis of Oligodehydroalanine Derivatives by Repetition of Stepwise Elongation of Serine Derivative and β-Elimination
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Facile and practical synthesis of various oligodehydroalanine and its amide derivatives, which compose most of the thiostrepton peptide antibiotics, were first accomplished by repetition of the stepwise elongation of serine derivative and then β-elimination.
- Shin, Chung-gi,Okumura, Kazuo,Ito, Akio,Nakamura, Yutaka
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p. 1301 - 1304
(2007/10/02)
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