Rutaecarpine-inspired scaffold-hopping strategy and Ullmann cross-coupling based synthetic approach: Identification of pyridopyrimidinone-indole based novel anticancer chemotypes.

Natural products as starting templates have shown historically major contribution to development of drugs. Inspired by the structure-function of an anticancer natural alkaloid Rutaecarpine, the Scaffold-hopped Acyclic Analogues of Rutaecarpine (SAAR) with 'N'-atom switch (1°-hop) and ring-opening (2°-hop) were investigated. A new synthetic route was developed for an effective access to the analogues, i.e. 2-indolyl-pyrido[1,2-a]pyrimidinones, which involved preparation of N-Boc-N'-phthaloyltryptamine/mexamine-bromides and pyridopyrmidinon-2-yl triflate, a nickel/palladium-catalysed Ullmann cross-coupling of these bromides and triflate, deprotection of phthalimide followed by N-aroylation, and Boc-deprotection. Fourteen novel SAAR-compounds were prepared, and they showed characteristic antiproliferative activity against various cancer cells. Three most active compounds (11a, 11b, and 11c) exhibited good antiproliferative activity, IC50 7.7-15.8 µM against human breast adenocarcinoma cells (MCF-7), lung cancer cells (A549), and colon cancer cells (HCT-116). The antiproliferative property was also observed in the colony formation assay. The SAAR compound 11b was found to have superior potency than original natural product Rutaecarpine and an anticancer drug 5-FU in antiproliferative activities with relatively lower cytotoxicity towards normal breast epithelial cells (MCF10A) and significantly higher inhibitory effect on cancer cells' migration. The compound 11b was found to possess favourable in silico physicochemical characteristics (lipophilicity-MLOGP, TPSA, and water solubility-ESOL, and others), bioavailability score, and pharmacokinetic properties (GI absorption, BBB non-permeant, P-gp, and CYP2D6). Interestingly, the compound 11b did not show any medicinal chemistry structural alert of PAINS and Brenk filter. The study represents for the first time the successful discovery of new potent anticancer chemotypes using Rutaecarpine natural alkaloid as starting template and reaffirms the significance of natural product-inspired scaffold-hopping technique in drug discovery research.

Stabilizing Bifurcated Hydrogen Bond in 8-Aminoquinoline Appended Peptides.

The hydrogen bonding interaction between an amide N-H and the amide N of the preceding residue is prevalent in proline-containing proteins and peptides. However, the N-H⋅⋅⋅N hydrogen bonding interaction is rare in non-prolyl natural peptides due to restricted dihedral angles. Herein, we stabilize this type of interaction in 8-aminoquinoline appended non-prolyl peptides through bifurcated N⋅⋅⋅H⋅⋅⋅N hydrogen bond. The 8-aminoquinoline-incorporated model peptides 2 a-i were designed, synthesized, and the crystal structures of 2 a-c and 2 i were solved. Analysis of crystal data reveals that the amide N-H of aminoquinoline is involved in bifurcated hydrogen bonding interaction with the nitrogen of the preceding amino acid residue and the nitrogen in quinoline. Analysis of crystal packing, Hirshfeld surface and fingerprint plots confirms that the intermolecular O⋅⋅⋅H contacts significantly contribute to stabilizing bifurcated N⋅⋅⋅H⋅⋅⋅N hydrogen bonding interaction. Furthermore, NMR experiments and CD spectroscopy were conducted to examine the preferred conformation in solution, and the data corroborate with the crystal structure conformation.

Molecular medicinal insights into scaffold hopping-based drug discovery success.

In both academia and the pharmaceutical industry, innovative hypotheses, methodologies and technologies that can shorten the drug research and development, leading to higher success rates, are vital. In this review, we demonstrate how innovative variations of the scaffold-hopping strategy have been used to create new druggable molecular spaces, drugs, clinical candidates, preclinical candidates, and bioactive agents. We also analyze molecular modulations that enabled improvements of the pharmacodynamic (PD), physiochemical, and pharmacokinetic (PK) properties (P3 properties) of the drugs resulting from these scaffold-hopping strategies.

Recent Insights into Nanoparticulate Carrier Systems of Curcumin and its Clinical Perspective in the Management of Various Health Issues.

Curcumin is a potent bioactive compound of Curcuma longa. Curcumin comprises a broad spectrum of biological activities, including hepatoprotective, anticancer, antimicrobial, anti-inflammatory, antitumor, anti-oxidant, etc. However, its low aqueous solubility, rapid excretion, and poor bioavailability restricted its therapeutic uses. To resolve these issues, novel nano-systems have now been developed to increase the bioactivity and bioavailability of curcumin by lowering the particle size, altering the surface, and increasing the efficacy of its encapsulation with various nanocarriers. Nanotechnology-based treatments can broaden the outlook for individuals with critical conditions. This article explores curcumin-based nanoparticulate carrier systems that should be employed to overcome this natural ingredient's inherent limitations. These nanocarriers also provide physical and chemical stability by encapsulating the drug into the core or matrix of the lipids or polymers. Nanotechnologists developed curcumin-encapsulated various nanoparticulate systems, including solid lipidic nanoparticles, polymeric nanoparticles, nano-structured lipid carriers, polymer conjugates, etc., to improve curcumin bioavailability and boost the sustained release of curcumin to target cells.

Defining the genes for the final steps in biosynthesis of the complex polyketide antibiotic mupirocin by Pseudomonas fluorescens NCIMB10586.

The mupirocin trans-AT polyketide synthase pathway, provides a model system for manipulation of antibiotic biosynthesis. Its final phase involves removal of the tertiary hydroxyl group from pseudomonic acid B, PA-B, producing the fully active PA-A in a complex series of steps. To further clarify requirements for this conversion, we fed extracts containing PA-B to mutants of the producer strain singly deficient in each mup gene. This additionally identified mupM and mupN as required plus the sequence but not enzymic activity of mupL and ruled out need for other mup genes. A plasmid expressing mupLMNOPVCFU + macpE together with a derivative of the producer P. fluorescens strain NCIMB10586 lacking the mup cluster allowed conversion of PA-B to PA-A. MupN converts apo-mAcpE to holo-form while MupM is a mupirocin-resistant isoleucyl tRNA synthase, preventing self-poisoning. Surprisingly, the expression plasmid failed to allow the closely related P. fluorescens strain SBW25 to convert PA-B to PA-A.