Fluorescein Hydrazones as Novel Nonintercalative Topoisomerase Catalytic Inhibitors with Low DNA Toxicity

Abstract

Fluorescein hydrazones (3a-3l) were synthesized in three steps with 86-91% overall yields. Topo I- and IIα-mediated relaxation and cell viability assay were evaluated. 3d inhibited 47% Topo I (camptothecin, 34%) and 20% Topo II (etoposide 24%) at 20 μM. 3l inhibited 61% Topo II (etoposide 24%) at 20 μM. 3d and 3l were further evaluated to determine their mode of action with diverse methods of kDNA decatenation, DNA-Topo cleavage complex, comet, DNA intercalating/unwinding, and Topo IIα-mediated ATP hydrolysis assays. 3d functioned as a nonintercalative dual inhibitor against the catalytic activities of Topo I and Topo IIα. 3l acted as a Topo IIα specific nonintercalative catalytic inhibitor. 3d activated apoptotic proteins as it increased the level of cleaved capase-3 and cleaved PARP in a dose- and time-dependent manner. The dose- and time-dependent increase of G1 phase population was observed by treatment of 3d along with the increase of p27(kip1) and the decrease of cyclin D1 expression.

A Series of Isatin-Hydrazones with Cytotoxic Activity and CDK2 Kinase Inhibitory Activity: A Potential Type II ATP Competitive Inhibitor

“…In this context, developing novel anticancer agents with great efficacy and high specificity becomes imperative. To overcome these challenges, researchers should develop a drug molecule with potent biological activity and low/no toxicity, study its mode of action, in silico properties and in vitro/vivo metabolism, conduct a toxicity evaluation [ 4 , 5 ], study its topoisomerase inhibitory activity [ 6 , 7 , 8 ] and enzyme inhibitory activity [ 9 ], etc., all of which are some of the key evaluation practices for the development of potential anticancer therapeutics. Regarding enzyme inhibitory activities, cyclin-dependent kinases (CDKs) are considered as a vital feature, inciting various key transitions in the cell cycle for cancer cells, in addition to instructing apoptosis, transcription and exocytosis.…”

“…It has been reported that tryptophan obtained from food sources is usually converted to indole by gastrointestinal bacteria, which is further oxidized in the liver by CYP450 to isatin, therefore, isatin is present as an endogenous molecule in humans [ 19 , 20 ]. Various substituents on the isatin nucleus displayed numerous biological activities [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ], including antimicrobial activity[ 31 , 37 ], topoisomerase inhibitory activity [ 7 , 38 ], epidermal growth factor receptor (EGFR) inhibitory activity [ 39 ], inhibitory activities on histone deacetylase (HDAC) [ 40 , 41 ], carbonic anhydrase [ 42 , 43 , 44 ], tyrosine kinase [ 45 , 46 , 47 ], cyclin-dependent kinases (CDKs) [ 9 , 48 , 49 ], adenylate cyclase inhibition [ 50 ] and protein tyrosine phosphatase (Shp2) [ 51 ]. A number of isatin-based marketed drugs and potential anticancer agents [ 41 ] are illustrated in Figure 1 .…”

Crystal structure of (E)-2-(((1H-pyrrol-2-yl)methylene)amino)-3′,6′-dihydroxyspiro[isoindoline-1,9′-xanthen]-3-one — methanol (1/2), C27H25N3O6

“…Fluorescein hydrazones have been paid much attention primarily due to their considerable biological activities [5] and excellent metal ions sensoring applications [4,[6][7][8]. Particularly, fluorescein hydrazone derived pyrrole-2-aldehyde is able to act as a fluorescent probe for turn-on detection of Cu 2+ ion [4].…”

Galeon: A Biologically Active Molecule with In Silico Metabolite Prediction, In Vitro Metabolic Profiling in Rat Liver Microsomes, and In Silico Binding Mechanisms with CYP450 Isoforms

“…Although a large number of natural/synthetic molecules have been reported to have potent biological activities, their further development is hampered due to the fact of their poor bioavailability and toxicity (i.e., generation of toxic reactive metabolites). Recently, a number of articles have been published reporting on the synthesis, biological evaluation, and metabolic profiling of natural/synthetic potential of drug molecules [4][5][6][7][8][9][10][11][12][13][14]. Galeon (Figure 1), a natural cyclic-diarylheptanoid (CDH), was first isolated from Myrica gale L. in 1976 by Malterud et al [13], and many other research groups have reported it from different plant species [11,12,[15][16][17][18][19][20][21][22], showing it to have potent biological activities; cytotoxicity against human cancer cell lines A549 (IC 50 = 2.2 µg/mL) [11], HL-60 (60.33 µmol/L), HeLa (58.21 µmol/L), Hepg2 (63.34 µmol/L) [21], T47D, MCF7, HCT15, and HeLa; anti-tubercular activity against Mycobacterium tuberculosis H37Rv in vitro (MIC = 15.0 µg/mL) [18]; chemo-preventive potential [23]; moderate topoisomerase inhibitory activity [4].…”