SYNTHESIS AND BIOLOGICAL ACTIVITIES OF NEW INDOLE DERIVATIVES CONTAINING SULFIDE AND/OR SULFONE MOIETIES. PART I

Abstract

4-Amino-halonitrodiphenyl sulfides(I) and/or 4-amino-halonitrodiphenyl sulfones have been found to react with isatin, N-acetyl isatin, isatin-N-Mannich bases, indole-3-carboxaldehyde and N-substituted indole-3-carboxaldehyde producing the corresponding indole derivatives. The biological activity of some of these products was screened against selected strains of bacteria.     

Novel Fluorinated Spiro [Indole-indazolyl-thiazolidine]-2,4′-diones: Design and Synthesis

The reaction of indol-2,3-diones ( 1a–i ) with 5-aminoindazole ( 2 ) has resulted in the formation of hitherto unknown 3-(indazol-5-yl)iminoindol-2-ones ( 3a–i ) in quantitative yields which, on 1,3-dipolar cyclocondensation with mercaptoacetic acid ( 4 ), has afforded a series of new spiro heterocycles, 3′-(indazol-5-yl) spiro[3H, indol-3, 2′ -thiazolidine]-2,4′-diones* ( 5a–i ).     

Studies on Organophosphorus Compounds XI: The Reaction of Phosphorus Reagents With Hydrazonoyl Halides,Hydrazonoyl Azides,and Shiff's Bases

N-(chloro-furan-2-yl)methylene-N′-(4-nitrophenyl)hydrazone (I) reacted with triethylphosphite to produce the phosphonate derivative III. The tetrazine derivative VI was produced by the interaction of I with diethyl-phosphite. Hydrazonoyl azide derivatives VIIIa–c reacted with triphenyl phosphine to form the iminophosphorane derivatives Xa–c. On the other hand, the azide derivative VIIIc reacted with the phosphonium ylide XI to form the 1,2,3-triazole adduct XIII. The reaction of triethyl phosphite with Shiff's bases XIVa–c yielded the corresponding phosphonates XVa–c. The structures of the newly prepared compounds were confirmed with the analytical and spectroscopic evidences.     

Synthesis and Incorporation of k2U into RNA

Lysidine (k²C) is one of the most modified pyrimidine RNA bases. It is a cytidine nucleoside, in which the 2-oxo functionality of the heterocycle is replaced by the ϵ-amino group of the amino acid lysine. As such, lysidine is an amino acid-containing RNA nucleoside that combines directly genotype (C-base) with phenotype (lysine amino acid). This makes the compound particularly important in the context of theories about the origin of life and here especially for theories that target the origin of translation. Here, we report the total synthesis of the U-derivative of lysidine (k²U), which should have the same base pairing characteristics as k²C if it exists in the isoC-like tautomeric form. To investigate this question, we developed a phosphoramidite building block for k²U, which allows its incorporation into RNA strands. Within RNA, k²U can base pair with the counter base U and isoG, confirming that k²U prefers an isoC-like tautomeric structure that is also known to dominate for k²C. The successful synthesis of a k²U phosphoramidite and its use for RNA synthesis now paves the way for the preparation of a k²C phosphoramidite and RNA strands containing k²C.     

Synthesis,Characterization, Crystal Structure,and Biological Activities of Transition Metal Complexes with 1‐Phenyl‐3‐methyl‐5‐hydroxypyrazole‐4‐methylene‐8′‐quinolineimine

The Schiff base ligand, 1‐phenyl‐3‐methyl‐5‐hydroxypyrazole‐4‐methylene‐8′‐quinolineimine, and its Cu^II, Zn^II, and Ni^II complexes were synthesized and characterized. The crystal structure of the Zn^II complex was determined by single‐crystal X‐ray diffraction, indicating that the metal ions and Schiff base ligand can form mononuclear six‐coordination complexes with 1:1 metal‐to‐ligand stoichiometry at the metal ions as centers. The binding mechanism and affinity of the ligand and its metal complexes to calf thymus DNA (CT DNA) were investigated by UV/Vis spectroscopy, fluorescence titration spectroscopy, EB displacement experiments, and viscosity measurements, indicating that the free ligand and its metal complexes can bind to DNA via an intercalation mode with the binding constants at the order of magnitude of 105–106 M ^–1, and the metal complexes can bind to DNA more strongly than the free ligand alone. In addition, antioxidant activities of the ligand and its metal complexes were investigated through scavenging effects for hydroxyl radical in vitro, indicating that the compounds show stronger antioxidant activities than some standard antioxidants, such as mannitol. The ligand and its metal complexes were subjected to cytotoxic tests, and experimental results indicated that the metal complexes show significant cytotoxic activity against lung cancer A 549 cells.     

Oxime Side‐Chain Cross‐Links in an α‐Helical Coiled‐Coil Protein: Structure,Thermodynamics, and Folding‐Templated Synthesis of Bicyclic Species

Covalent side‐chain cross‐links are a versatile method to control peptide folding, particularly when α‐helical secondary structure is the target. Here, we examine the application of oxime bridges, formed by the chemoselective reaction between aminooxy and aldehyde side chains, for the stabilization of a helical peptide involved in a protein–protein complex. A series of sequence variants of the dimeric coiled coil GCN4‐p1 bearing oxime bridges at solvent‐exposed positions were prepared and biophysically characterized. Triggered unmasking of a side‐chain aldehyde in situ and subsequent cyclization proceed rapidly and cleanly at pH 7 in the folded protein complex. Comparison of folding thermodynamics among a series of different oxime bridges show that the cross links are consistently stabilizing to the coiled coil, with the extent of stabilization sensitive to the exact size and structure of the macrocycle. X‐ray crystallographic analysis of a coiled coil with the best cross link in place and a second structure of its linear precursor show how the bridge is accommodated into an α‐helix. Preparation of a bicyclic oligomer by simultaneous formation of two linkages in situ demonstrates the potential use of triggered oxime formation to both trap and stabilize a particular peptide folded conformation in the bound state.     

Synthesis,Structure, and Reactivity of Lewis Base Stabilized Plumbacyclopentadienylidenes

Plumbacyclopentadienylidenes, in which the lead atoms have divalent states and are coordinated by THF, pyridine and N‐heterocyclic carbene, were synthesized and characterized. The THF‐ and pyridine‐stabilized compounds can be regarded as rare examples of hypervalent 10‐X‐4 species. The equilibrium between the THF adduct and the free plumbacyclopentadienylidene was evidenced by spectroscopic analysis and theoretical calculations. The THF adduct in benzene converted into a plumbylene dimer, where one of the lead centers is coordinated by THF and the other lead atom is coordinated by a divalent lead atom, the dimer gradually decomposing into spiroplumbole. The THF adduct unexpectedly reacted with trifluoroborane and trichlorogallane to afford fluoroborole and chlorogallole, which are the first examples of non‐annulated fluoroborole and gallole, respectively.     

Synthesis of Some Novel bis‐Spiro[indole‐pyrazolinyl‐thiazolidine]‐2,4′‐diones

The reaction of 1H‐indol‐2,3‐diones with 1,6‐dibromohexane has resulted in the formation of new 1H‐indol‐2,3‐diones‐1,1′‐(1,6‐hexanediyl)bis in quantitative yields. These compounds have been used for the synthesis of novel [3′‐(2,3‐dimethyl‐5‐oxo‐1‐phenyl‐3‐pyrazolin‐4‐yl)spiro[3H‐indol‐3,2′‐thiazolidine]‐2,4′‐dione]‐1,1′‐(1,6‐hexanediyl)bis via bis Schiff's bases, [3‐(2,3‐dimethyl‐5‐oxo‐1‐phenyl‐3‐pyrazolin‐4‐yl) imino‐1H‐indol‐2‐one]‐1,1′‐(1,6‐hexanediyl)bis.     

2-Keto-3-mercaptocinchoninic Acids as Precursors for Novel Thiazino[6,5-c]quinoline-1,5-dione Derivatives

2-Keto-3-mercaptocinchoninic acid derivatives 1a and b react with Schiff's bases 2a–d in toluene at refluxing temperature to give thiazino[6,5-c]quinoline derivatives 4a–h. Also, refluxing of 1a and b with arylazomalononitriles 5a–d in acetic acid afforded the thiazolo[6,5-c]quinoline derivatives 7a–d. The structure of all the newly synthesized products was confirmed based on elemental and spectral data.     

Lewis Base Catalysis of the Mukaiyama Directed Aldol Reaction: 40 Years of Inspiration and Advances

Since the landmark publications of the first directed aldol addition reaction in 1973, the site, diastereo‐, and enantioselective aldol reaction has been elevated to the rarefied status of being both a named and a strategy‐level reaction (the Mukaiyama directed aldol reaction). The importance of this reaction in the stereoselective synthesis of untold numbers of organic compounds, both natural and unnatural, cannot be overstated. However, its impact on the field extends beyond the impressive applications in synthesis. The directed aldol reaction has served as a fertile proving ground for new concepts and new methods for stereocontrol and catalysis. This Minireview provides a case history of how the challenges of merging site selectivity, diastereoselectivity, enantioselectivity, and catalysis into a unified reaction manifold stimulated the development of Lewis base catalyzed aldol addition reactions. The evolution of this process is chronicled from the authors’ laboratories as well as in those of Professor Teruaki Mukaiyama.