Recent Advances in the Chemistry and Therapeutic Evaluation of Naturally Occurring and Synthetic Withanolides

Natural products are a major source of biologically active compounds that make promising lead molecules for developing efficacious drug-like molecules. Natural withanolides are found in many flora and fauna, including plants, algae, and corals, that traditionally have shown multiple health benefits and are known for their anti-cancer, anti-inflammatory, anti-bacterial, anti-leishmaniasis, and many other medicinal properties. Structures of these withanolides possess a few reactive sites that can be exploited to design and synthesize more potent and safe analogs. In this review, we discuss the literature evidence related to the medicinal implications, particularly anticancer properties of natural withanolides and their synthetic analogs, and provide perspectives on the translational potential of these promising compounds.     

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone,a Nicotine-derived Carcinogenic Nitrosaminoketone (NNK): Three-dimensional Structure

The three-dimensional structure of the carcinogenic nicotine-derived nitrosaminoketone, 4-(methyl-nitrosamino)-l-(3-pyridyl)-l-butanone, has been determined by X-ray crystallographic techniques. The molecule is essentially planar except for the methylnitrosamine group which is oriented at a dihedral angle of 68.7° to the pyridine ring. Molecules pack by way of —HO interactions that involve the —NNO group.     

Convenient syntheses of dibenzo[c,p]chrysene and its possible proximate and ultimate carcinogens: in vitro metabolism and DNA adduction studies

Dibenzo[c,p]chrysene (DB[c,p]C) is the only hexacyclic polycyclic aromatic hydrocarbon having two fjord regions, both in different chemical environments. Its environmental presence and relative tumorigenic potency are not known due to the lack of synthetic standards. We report here the synthesis of dibenzo[c,p]chrysene (1), its proximate carcinogens, i.e., trans-1,2-dihydroxy-1,2-dihydro-DB[c,p]C (2) and trans-11,12-dihydroxy-11,12-dihydro-DB[c,p]C (3), and possible ultimate carcinogens, i.e., anti-trans-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-DB[c,p]C (4) and anti-trans-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydro-DB[c,p]C (5). The syntheses of 1 and the appropriately methoxy-substituted DB[c,p]C (12 and 27), key intermediates for the synthesis of its proximate and ultimate metabolites, were tried first using a Suzuki cross-coupling reaction. However, the cyclization of olefins (10 and 11) gave poor yields of the desired products. An alternate method was thus developed employing a photochemical approach. The in vitro metabolism of DB[c,p]C was established with the S9 fraction of liver homogenate from phenobarbital/beta-naphthoflavone-induced Sprague-Dawley rats. The major dihydrodiol formed was identified as the fjord region 11,12-dihydroxy-11,12-dihydro-DB[c,p]C, while the major and minor phenols were identified as 11-hydroxy-DB[c,p]C and 12-hydroxy-DB[c,p]C, respectively. Further, the DNA adduction studies with the calf thymus DNA led to a mixture of dA and dG adducts for both fjord region diol epoxides (4 and 5). Interestingly, the dA to dG ratio for 1,2-dihydroxy-3,4-epoxide was much higher (3.2) compared to that of 11,12-dihydroxy-13,14-epoxide (0.5).     

Deterministic inhomogeneous inertia ratchets

We study the deterministic dynamics of a periodically driven particle in the underdamped case in a spatially symmetric periodic potential. The system is subjected to a space-dependent friction coefficient, which is similarly periodic as the potential but with a phase difference. We observe that frictional inhomogeneity in a symmetric periodic potential mimics most of the qualitative features of deterministic dynamics in a homogeneous system with an asymmetric periodic potential. We point out the need of averaging over the initial phase of the external drive at small frictional inhomogeneity parameter values or analogously low potential asymmetry regimes in obtaining ratchet current. We also show that at low amplitudes of the drive, where ratchet current is not possible in the deterministic case, noise plays a significant role in realizing ratchet current.     

A Highly Abbreviated Synthesis of Dibenzo[def,p]chrysene and Its 12-Methoxy Derivative, a Key Precursor for the Synthesis of the Proximate and Ultimate Carcinogens of Dibenzo[def,p]chrysene

Dibenzo[def,p]chrysene (DBC) (1), is by far the most mutagenic and toxic polycyclic aromatic hydrocarbon identified. Its metabolic activation leads to trans-11,12-dihydroxy-11,12-dihydro-DBC (2), which is further metabolized to the ultimate metabolite, anti-trans-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydro-DBC (3), that binds to DNA causing mutations and ultimately tumor induction. We report a facile route for the syntheses of DBC (1) and its 12-methoxy derivative (12-methoxy-DBC) (13), a key intermediate for the synthesis of 2 and 3, using a Suzuki cross-coupling approach.     

Microwave-assisted Suzuki cross-coupling reaction, a key step in the synthesis of polycyclic aromatic hydrocarbons and their metabolites

A highly efficient and general method for Suzuki cross-coupling reaction en route to the synthesis of polycyclic aromatic hydrocarbons (PAHs) and their metabolites has been developed. Microwave irradiation of aryl bromides 1 and boronic acids (2 and 3) using polyurea microencapsulated palladium catalyst (Pd EnCat 30) gave the coupling adducts 4 and 5 in excellent yields in just 20 min compared to approximately 24 h under thermal conditions, corresponding to a approximately 72-fold increase in reaction rate.