Nanoformulation of a Novel Pyrano[2,3-c] Pyrazole Heterocyclic Compound AMDPC Exhibits Anti-Cancer Activity via Blocking the Cell Cycle through a P53-Independent Pathway

Abstract

Pyrano[2,3-c]pyrazole derivatives have been reported as exerting various biological activities. One compound with potential anti-tumor activity was screened out by MTT assay from series of dihydropyrazopyrazole derivatives we had synthesized before using a one-pot, four-component reaction, and was named as 6-amino-4-(2-hydroxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (hereinafter abbreviated as AMDPC). The IC50 of AMDPC against Bcap-37 breast cancer cells was 46.52 μg/mL. Then the hydrophobic AMDPC was encapsulated in PEG-PLGA block copolymers, and then self-assembled as polymeric micelle (mPEG-PLGA/AMDPC) to improve both physiochemical and release profiles. The effect of mPEG-PLGA/AMDPC on BCAP-37 cancer cells showed similar anti-tumor effects as AMDPC. Furthermore, the anti-tumor mechanism of mPEG-PLGA/AMDPC was investigated, which can probably be attributed to stimulating the expression of P21 gene and therefore protein production on BCAP-37 cells, and then blocked the cell cycle through the P53-independent pathway both in S phase and G2 phase. Thus, mPEG-PLGA/AMDPC is a promising therapeutic agent for cancer treatment, and further in vivo studies will be developed.

Preparation and Physicochemical Characterization of Water-Soluble Pyrazole-Based Nanoparticles by Dendrimer Encapsulation of an Insoluble Bioactive Pyrazole Derivative

“…The DL% of BBB4-G4K was very high, thus making possible a great bioactivity at a minimal dosage of the formulation. In fact, the DL% of BBB4-G4K NPs was 22.5-fold higher than that obtained recently by Sun et al [ 13 ], encapsulating the pyrazole derivative 6-amino-4-(2-hydroxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (AMDPC) in the commercial polymers poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) (PEG-PLGA), and obtaining micelles with DL% = 1.28. On the contrary, the EE% of BBB4-G4K was lower than that of the micelles [ 13 ].…”

“…Experiments to evaluate of the cytotoxicity of BBB4 on normal cells (human keratinocytes HaCaT) are currently undergoing. In any case, to have an idea of the cytotoxic effects of pyrazole-based compounds, we have herein reported ( Table 1 ) the cytotoxicity data found in the literature of some pyrazole derivatives on different human cancer cell lines such as A549 (lung cancer), HeLa (cervical cancer), MCF-7, and BCAP-37 (breast cancer) and a normal cell line (human embryonic kidney HEK-293) [ 13 , 24 ].…”

“…To our knowledge, only two studies exist in the literature concerning the nano-encapsulation of two out of the several reported bioactive pyrazole derivatives poorly soluble in water [ 12 , 13 ], but only one concerns a nanotechnology application to enhance water solubility [ 13 ]. In particular, Sun et al [ 13 ] have recently encapsulated the pyrazole derivative 6-amino-4-(2-hydroxyphenyl)-3-methyl-1,4-dihydropyrano [2,3-c] pyrazole-5-carbonitrile (AMDPC) in commercial polymers, poly (ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) (PEG-PLGA), obtaining micelles which gave clear water solutions at 0.05 mg/mL, while at the same concentration, pristine AMDPC was insoluble. Although AMDPC was turned water soluble, considering the very low DL% (1.28) obtained in this study, the water solubility obtained for the encapsulated AMDPC was insignificant (0.64 × 10 −4 mg/mL).…”

Synthesis and Biological Activities of Some New Phosphorus Compounds Containing Pyranopyrazole Moiety

“…15 In this context, pyranopyrazole systems have well been recognized for their potent biological activities including antimicrobial, 16 antioxidant, 17 antiviral 18 and antitumor. 19 Recently, we studied the reaction of the 6-amino-3-methyl-1,4-diphenyl-1,4-dihydropyrano-[2,3-c]pyrazole-5-carbonitrile (3) with some phosphorus halides. 20 Considering the above mentioned, we herein study the chemical reactivity of substrate 3 towards some other phosphorus amide and phosphorus esters in the presence of electrophilic reagents in a one-pot and three-components.…”

Synthesis of pyrano[2,3‐c]pyrazoles: A review

“…Dihydropyrano[2,3‐c]pyrazole 1 nucleus is a fruitful source of several medicinally important compounds because of its diverse bioactivities, such as anti‐inflammatory, [ 8,9 ] anticancer, [ 10–12 ] antioxidant, [ 13–15 ] anti‐cholinesterase, [ 16 ] analgesic, [ 9 ] antimicrobial activity, [ 17–20 ] and also act as human checkpoint kinase 1 (Chk1) inhibitor 5 (Figure 2). [ 21 ]…”