A new approach to the 8b-azaacenaphthylene ring system.

A stereoselective approach to the 8b-azaacenaphthylene ring system is described. This new route features a dichloroketene-enol ether [2 + 2] cycloaddition, a vinylogous Mannich reaction, and an aza-Prins cyclization as key stereoselective transformations.

Asymmetric approach to hyacinthacines B1 and B2.

Naturally occurring hyacinthacines B1 and B2 have been prepared from a common, easily available, advanced intermediate. The approach features several highly stereoselective transformations: inter alia, a dichloroketene-enol ether [2 + 2] cycloaddition, a Bruylants alkylation, and an amino-nitrile alkylation-reduction.

Rogue one: A plastic story.

Plastic comprises of variety of polymers and has many applications, but the waste generated by plastic pose threat to environment and marine life. Plastic can be classified into two types: thermoplastics and thermosetting and are divided into 7 different categories: (Polyethylene Terephthalate [PETE], High-Density Polyethylene [HDPE], Polyvinyl Chloride [PVC], Low-Density Polyethylene [LDPE], Polypropylene [PP], Polystyrene or Styrofoam [PS] & Polycarbonate or ABS [others]). To curb the deleterious effects of plastic waste various methods have been devised and utilized that include chemical, physical and biological treatments. One of the aspects primarily focused by the researchers is the phenomenon of biodegradation and there are many microorganisms (bacteria) that have the ability to carry out this particular process. These bacteria assist biodegradation by production of several enzymes like PETases and MHETases. There are few microorganisms that have been listed which cannot be applied for industrial use due to its low biodegradation capacity. To overcome this problem, PHA is one of the alternatives to replace the synthetic plastic due to its high degrading capacity.

CRISPR: The Multidrug Resistance Endgame?

The flexibility of microbes to undergo or adapt to the changes in their physiology and genotypical traits has enabled the microbes acquiring resistance to latest or recently discovered drugs which have consequently led to the menace of multidrug resistance (MDR). There is a surge in the discovery of novel antibiotics to counter the rising MDR phenomena, and in such a quest, for investigating an efficient alternative mechanism or compound to combat MDR, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) has piqued the interests of the researchers across the globe. CRISPR-Cas9 technology is a genome-editing tool with successful widespread applications in cell lines, plants, animals, and even in human clinical trials, and it is seriously being considered as a potential candidate for countering MDR. This review encompasses the broad scope of CRISPR-Cas9 along with its various variations, underlying principles, mechanisms, as well as applications. Furthermore, the implications of recent advancements in various disciplines are highlighted to enhance the applicability of this technique. Consequently, its research gaps and challenges are also identified so that they can be addressed in the possible future thereby further expanding the lore of CRISPR-Cas9 technique.

Targeting the Hemopexin-like Domain of Latent Matrix Metalloproteinase-9 (proMMP-9) with a Small Molecule Inhibitor Prevents the Formation of Focal Adhesion Junctions.

A lack of target specificity has greatly hindered the success of inhibitor development against matrix metalloproteinases (MMPs) for the treatment of various cancers. The MMP catalytic domains are highly conserved, whereas the hemopexin-like domains of MMPs are unique to each family member. The hemopexin-like domain of MMP-9 enhances cancer cell migration through self-interaction and heterointeractions with cell surface proteins including CD44 and α4ß1 integrin. These interactions activate EGFR-MAP kinase dependent signaling that leads to cell migration. In this work, we generated a library of compounds, based on hit molecule N-[4-(difluoromethoxy)phenyl]-2-[(4-oxo-6-propyl-1H-pyrimidin-2-yl)sulfanyl]-acetamide, that target the hemopexin-like domain of MMP-9. We identify N-(4-fluorophenyl)-4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-ylthio)butanamide, 3c, as a potent lead (Kd = 320 nM) that is specific for binding to the proMMP-9 hemopexin-like domain. We demonstrate that 3c disruption of MMP-9 homodimerization prevents association of proMMP-9 with both α4ß1 integrin and CD44 and results in the dissociation of EGFR. This disruption results in decreased phosphorylation of Src and its downstream target proteins focal adhesion kinase (FAK) and paxillin (PAX), which are implicated in promoting tumor cell growth, migration, and invasion. Using a chicken chorioallantoic membrane in vivo assay, we demonstrate that 500 nM 3c blocks cancer cell invasion of the basement membrane and reduces angiogenesis. In conclusion, we present a mechanism of action for 3c whereby targeting the hemopexin domain results in decreased cancer cell migration through simultaneous disruption of α4ß1 integrin and EGFR signaling pathways, thereby preventing signaling bypass. Targeting through the hemopexin-like domain is a powerful approach to antimetastatic drug development.

Design, synthesis, and biological evaluations of tumor-targeting dual-warhead conjugates for a taxoid-camptothecin combination chemotherapy.

Novel tumor-targeting dual-warhead conjugates, 2 (DW-1) and 3 (DW-2), which consist of a next-generation taxoid, 1 (SB-T-1214), and camptothecin as two warheads, self-immolative disulfide linkers for drug release, biotin as the tumor-targeting moiety, and 1,3,5-triazine as the tripod splitter module, were designed and synthesized. The potency of 2 was evaluated against MX-1, MCF-7, ID8, L1210FR (BR+, biotin receptor overexpressed) and WI38 (BR-, normal) cell lines in the absence and presence of glutathione (GSH), which is an endogenous thiol that triggers drug release inside the cancer cells. With the GSH and resuspension protocol, 2 exhibited IC50 values of 3.22-9.80 nM against all BR+ cancer cell lines, and 705 nM against WI38. Thus, there was a two orders of magnitude higher selectivity to cancer cells. Also, a clear cooperative effect was observed for the taxoid-camptothecin combination when two drugs were delivered to the cancer cells specifically in the form of a dual-warhead conjugate.