Synthesis and Biological Activity of a Novel Pentacyclic Heterocycle

A novel pentacyclic heterocycle has been synthesized starting from D ‐glucose involving two crucial conversions: the intramolecular cycloaddition of O‐allyloxy furanaldoxime derived from D ‐glucose to furanopyran‐2‐isoxazoline and its diastereoselective reductive cleavage to the corresponding cis‐1,3‐amino alcohol. The antibacterial and antifungal activities of the synthesized heterocycle have been examined.     

Isolation,structural assignment and synthesis of (SE)-2-methyloctyl 3-(4-methoxyphenyl) propenoate from the marine soft coral Sarcophyton ehrenbergi

A new metabolite 1 has been isolated from the marine soft coral Sarcophyton ehrenbergi along with two known diterpenoids 2 and 3 and cholesterol 4. The structure of 1 was determined by means of detailed spectroscopic analysis and unambiguously confirmed to have the S configuration by the synthesis of both enantiomers using 4-benzyl-2-oxazolidinone auxiliaries. (S)- and (R)-1, 3 and some of the synthetic intermediates were evaluated for cytotoxic activity against human lung cancer (A549), prostate cancer (DU145), cervical cancer (HeLa) and breast cancer (MCF-7) cell lines in an in vitro bioassay.     

Interesting transformations of naturally occurring cassane diterpenoids and bioevaluation of the products

Two cassane diterpenoids, pulcharrin G (1) and 6β-cinnamoyl-7β-hydroxy-voucapen-5-α-ol (2), the constituents of Caesalpinia pulcherrima, were treated with BF₃·OEt₂ to furnish two olefinic products 3 and 4, respectively. The products were formed by elimination of water and migration of a methyl group from C-4 to C-5. The cytotoxic and antimicrobial activities of 3 and 4 were examined.     

Isomeric ent‐Labdane‐Type Diterpenoids from the Stems of Rhizophora mucronata

Two new constitutional isomers of ent‐labdane‐type diterpenoids, 1 and 2 , with an unusual seven‐membered lactone moiety (i.e., 1 ), together with two known compounds, 3 and 4 , were isolated from the acetone extract of Rhizophora mucronata. Their structures were elucidated as rhizomucronol A and B ( 1 and 2 , resp.) by spectroscopic analyses and chemical evidence. The absolute configuration of 2 was established by applying the Mosher ester procedure.     

Synthesis and biological evaluation of 1,2,4-oxadiazole linked 1,3,4-oxadiazole derivatives as tubulin binding agents

As an aspect of our ongoing research in search of new anticancer agents, a series of novel analogs of 1,3,4-oxadiazole embedded with 1,2,4-oxadiazole moieties (11a–j) were synthesized. The structure of the final compounds was confirmed by ¹H NMR, ¹³CNMR and mass spectroscopic techniques and evaluated for their in vitro anticancer activity against three human cancer cell lines (lung, breast). Among the synthesized compounds, 11?b, 11?g, 11?h, and 11i showed potent anticancer activity with IC₅₀ values within the range of 0.34?±?0.025 to 2.45?±?0.23?μM against three human cancer cell lines. Further, these compounds (11a–j) were investigated for molecular docking studies. Among them, compound 11?h showed strong binding affinity on binding sites of target protein EGFR (PDB ID: 4hjo) with highest docking score (-7.028). It revealed that 11?h was a strong tubulin binding agent.     

Aromatic interaction profile to understand the molecular basis of raltegravir resistance

Integrase (IN) is the enzyme of human immunodeficiency virus (HIV) which inserts the viral DNA (vDNA) into the host genome for successful viral replication leading to the infection. However, the chemical basis of HIV IN catalysis is speculative due to lack of complete co-crystal structure. Using the recently published prototype foamy virus IN crystal structure, we developed a model structure of HIV IN showing interaction of vDNA, the metal (Mg²⁺) cofactor, and raltegravir (RLT) in the active site. Molecular docking and dynamics simulations studies showed that RLT uses it core central ring with diketo motif for Mg²⁺ chelation and bridge interaction with DDE motif. The triple arene interactions mediated by RLT with neighboring molecular motifs (Y143, cytosine, and adenine) is maintained during long simulation in wild type (WT). The fluorobenzyl and oxadiazole moieties of RLT forms aromatic stacking with cytosine base (head stacking) aromatic side chain of Y143 (tail stacking), respectively, while central ring further establishes aromatic stacking with distorted adenine base of vDNA (central stacking). The novel triple stacking systems were further explored to understand the molecular basis of drug resistance by molecular simulation. The in silico mutation (N155H, Q148H, and Q148H + G140S) and simulation studies elucidated the structural mechanism of resistance to RLT. The simulation studies provided the molecular basis for interdependency observed for the primary and secondary (Q148H and G140S) mutations and also explained the mechanism of viral fitness regain. Our study reveals that triple stacking and its consequence in terms of VdW energetic profile acts as a critical point to understand the drug-resistance. Here, we demonstrate that the root mean square deviation of centroid system (aromatic stacking) can be used as a major determinant of RLT binding toward the fold resistance. This is first kind of report, which discloses a strategy to explore the molecular level of drug resistance profile using aromatic interactions.     

A Benzofuranoid and Two Clerodane Diterpenoids from Pulicaria wightiana

Methyl 5‐formyl‐1‐benzofuran‐6‐carboxylate ( 1 ) and the two clerodane diterpenes, methyl 6‐oxocleroda‐3,13‐dien‐15,16‐olid‐18‐oate ( 2 ) and 2β‐(2‐methylbutanoyl)cleroda‐3,13‐dien‐15,16‐olid‐18‐oic acid ( 3 ), together with 15 known compounds, were isolated from the aerial parts of Pulicaria wightiana. The structures of the new compounds 1, 2 , and 3 were established by spectroscopic (mainly 1D‐ and 2D‐NMR) methods.