1,3,4-Oxadiazole-containing hybrids as potential anticancer agents: Recent developments,mechanism of action and structure-activity relationships

Chemotherapy is an important therapeutic approach for the treatment of cancer. Currently, many anticancer drugs are available in the market that plays an important role in cancer treatment, but concerns such as, drug resistance and side effects create an urgent need for the development of new anti-tumor drugs with high potency and less side effects. Heterocycles are of great interest due to their fascinating anticancer activity. Among them, 1,3,4-oxadiazoles showed attracting anti-tumor activity and its derivatives are under clinical trials for the treatment of cancer. Hybridization of 1,3,4-oxadiazole moiety with other heterocyclic pharmacophoresis a promising approach to overcome various disadvantages of current anticancer drugs such as drug resistance, toxicity, and other side effects. Thus, 1,3,4-oxadiazole-heterocycle hybrids occupy a significant position in the discovery of anti-tumor drugs. Among the reported oxadiazole-based hybrids reviewed here, compounds 45i, 59j, and 62x showed the highest anticancer activity with IC₅₀ values in the nanomolar range. This review summarizes the recent developments in the anticancer potential, structure–activity relationships, and mechanisms of actions of 1,3,4-oxadiazole-heterocycle hybrids.     

2‐Aminoethanol Extraction as a Method for Purifying Sc3N@C80 and for Differentiating Classes of Endohedral Fullerenes on the Basis of Reactivity

Extraction with 2‐aminoethanol is an inexpensive method for removing empty cage fullerenes from the soluble extract from electric‐arc‐generated fullerene soot that contains endohedral metallofullerenes of the type Sc₃N@C_2n (n=34, 39, 40). Our method of separation exploits the fact that C₆₀, C₇₀, and other larger, empty cage fullerenes are more susceptible to nucleophilic attack than endohedral fullerenes and that these adducts can be readily extracted into 2‐aminoethanol. This methodology has also been employed to examine the reactivity of the mixture of soluble endohedral fullerenes that result from doping graphite rods used in the Krätschmer–Huffman electric‐arc generator with the oxides of Y, Lu, Dy, Tb, and Gd. For example, with Y₂O₃, we were able to detect by mass spectrometry several new families of endohedral fullerenes, namely Y₃C₁₀₈ to Y₃C₁₂₆, Y₃C₁₀₇ to Y₃C₁₂₅, Y₄C₁₂₈ to Y₄C₁₄₆, that resisted reactivity with 2‐aminoethanol more than the empty cage fullerenes and the mono‐ and dimetallo fullerenes. The discovery of the family Y₃C₁₀₇ to Y₃C₁₂₅ with odd numbers of carbon atoms is remarkable, since fullerene cages must involve even numbers of carbon atoms. The newly discovered families of endohedral fullerenes with the composition M₄C_2n (M=Y, Lu, Dy, Tb, and Gd) are unusually resistant to reaction with 2‐aminoethanol. Additionally, the individual endohedrals, Y₃C₁₁₂ and M₃C₁₀₂ (M=Lu, Dy, Tb and Gd), were remarkably less reactive toward 2‐aminoethanol.     

Predicting Stable Molecular Structures for (RNC)2AuIX Complexes

Calculations have been performed at the MP2 and DFT levels for investigating the reasons for the difficulties in synthesizing bis(isocyanide)gold(I) halide complexes. Three‐coordinated gold(I) complexes of the type (R₃P)₂Au^IX ( 1 ) can be synthesized, whereas the analogous isocyanide complexes (RNC)₂Au^IX ( 2 ) are not experimentally known. The molecular structures of (R₃P)₂Au^IX (X = Cl, Br, and I) and (RNC)₂Au^IX with X = halide, cyanide, nitrite, methylthiolate, and thiocyanate are compared and structural differences are discussed. Calculations of molecular properties elucidate which factors determine the strength of the gold‐ligand interactions in (RNC)₂Au^IX. The linear bonding mode of RNC favors a T‐shaped geometry instead of the planar Y‐shaped trigonal structure of (R₃P)₂Au^IX complexes that have been synthesized. An increased polarity of the Au–X bond in 2 leads to destabilization of the Y‐shaped structure. Chalcogen‐containing ligands or cyanide appear to be good X‐ligand candidates for synthesis of (RNC)₂Au^IX complexes.     

A Dumbbell Shaped Fullerene Dimer with An Inorganic Linker. Addition of C60 and Tetracyanoethylene to Ir2(CO)2Cl2(Ph2P(CH2)nPPh2)2 (n=5 or 7)

The centrosymmetric dimers, ( ²-C₆₀)₂Ir₂(CO)₂Cl₂(-Ph₂P(CH₂)₇PPh₂)₂ and ( ²-TCNE)₂Ir₂(CO)₂Cl₂(-Ph₂P(CH₂)₅PPh₂)₂, have been prepared by the reactions of C₆₀ with Ir₂(CO)₂Cl₂(-Ph₂P(CH₂)₇PPh₂)₂ and of tetracyanoethylene (TCNE) with Ir₂(CO)₂Cl₂(-Ph₂P(CH₂)₅PPh₂)₂, respectively. The structures of both adducts have been elucidated by single crystal X-ray diffraction studies.     

Crystallographic characterization of the structure of the endohedral fullerene [Er2@C82 isomer I] with C(s) cage symmetry and multiple sites for erbium along a band of ten contiguous hexagons

The structure of one of the three previously separated isomers of {Er2@C82} has been determined through a single-crystal X-ray structure determination of the noncovalent adduct, {Er2@C82 Isomer I}.{CoII(OEP)}.1.4(C6H6).0.3(CHCl3). The C82 cage is identified specificlly as the Cs(82:6) isomer (one of nine possible isolated pentagon isomers) from the crystallographic data. The carbon atoms of the C82 cage were individually identified and refined with only a constraint that required the two halves of the cage to possess similar bond lengths. Although the carbon cage is well ordered at 113 K, the erbium atoms are disordered. The electron density within the cage of {Er2@C82 Isomer I} has been modeled with two major sites with occupancies of 0.35 and 21 other individual erbium sites with occupancies ranging from 0.138 to 0.011. These erbium sites all reside near the walls of the fullerence and cluster near a band of ten contiguous hexagons that encircles the carbon cage. Since two other isomers of C82 (C3v(82:8) and C2v(82:9)) have a similar band of ten contiguous hexagons, it is tempting to speculate that the other two known isomers of {Er2@C82} have these cage structures.     

Aurophilic interactions in cationic gold complexes with two isocyanide ligands. Polymorphic yellow and colorless forms of [(cyclohexyl isocyanide)2AuI](PF6) with distinct luminescence

Crystallographic studies of yellow and colorless forms of [(C(6)H(11)NC)(2)Au(I)](PF(6)) show that they are polymorphs with differing, but close, contacts between the gold atoms which form extended chains. In the colorless polymorph the gold cations form linear chains with a short Au...Au contact (3.1822(3) A) indicative of an aurophilic attraction. The structure of the yellow polymorph is more complicated with four independent cations forming kinked, slightly helical chains with very short Au...Au contacts of 2.9803(6), 2.9790(6), 2.9651(6), and 2.9643(6) A. However, in the related compound, [(CH(3)NC)(2)Au(I)](PF(6)), each cation is surrounded by six hexafluorophosphate ions and there is no close Au...Au contact despite the fact that the isocyanide ligand has less steric bulk. The crystalline colorless and yellow polymorphs are both luminescent at 298 K, lambda(max): 424 nm (colorless) or 480 nm (yellow). Colorless solutions of the two polymorphs have identical absorption spectra and are nonluminescent at room temperature. Freezing solutions of [(C(6)H(11)NC)(2)Au(I)](PF(6)) produces intense luminescence which varies depending upon the solvent involved. Each polymorph melts to give a colorless but luminescent liquid which reverts to the yellow polymorph upon cooling.     

Reversible binding of nitric oxide and carbon-carbon bond formation in a meso-hydroxylated heme

Exposure of a pyridine solution of (py)2Fe(OEPO) (1) (OEPO is the trianion of octaethyloxophlorin, py is pyridine) at 22 degrees C to nitric oxide under the strict exclusion of dioxygen results in a color change from green to red-brown and the formation of {(py)(ON)Fe(OEPO)}2 (2). Monitoring the reaction by 1H NMR spectroscopy shows that the reaction is reversible. The air-sensitive product {(py)(ON)Fe(OEPO)}2 has been isolated and characterized by X-ray crystallography. NO binding is accompanied by association of two hemes through the formation of a new C-C bond between two meso carbon atoms on the porphyrin periphery. The macrocyclic ligand has a ruffled distortion that positions the C5-O1 group with its short C=O bond distance (1.237(3) A) in close proximity to the NO ligand. Since further attack upon 1 by O2 during heme degradation involves reaction in the vicinity of the oxygenated meso position, the positioning of the NO ligand so that the O2...C5 distance is only 3.100(3) A presents a highly suggestive model for the next stage of attack upon the heme periphery.