INHIBITION OF VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2 BY CHALCONES
Depending on the type of vertebrate species, the genes of VEGFR comprises of 3-4 members. It comprises of three loops produced by the intramolecular disulfide bonding, and loop 1 cooperates with loop 3 to exhibit necessary binding and activation cascade for angiogenic switching (Sawamiphak et al., 2010). VEGFR-1 (VEGF receptor 1 also known as Flt-1, fins-like tyrosine kinase) and VEGFR-2 (KDR/Flk-1, fetal liver kinase 1 is the murine homolog of human kinase insert domain-containing receptor) are the most prominent receptors involved in vasculogenesis, neovascularization, and proangiogenesis processes (Figure 11.3) (D'Haene et al., 2013). VEGFR-2 is a receptor of VEGF-A and mostly mediates endothelial growth and signaling. The angiogenic promoters are foremost expressed by VEGF-E (Orf-virus-derived VEGF) (Li et al., 2005). The inhibition of VEGFR-2 may be regarded as the most fitting biological target for the suppression of solid tumors (Shibuya, 2006). Researchers working on chalcone scaffold have put forward some recently tested VEGFR-2 inhibitors as perspective antiangiogenic agents.
FIGURE 11.3 Illustration of the VEGFR-2 pathway.
Based on the structure-based virtual screening, quinolyl-thienyl chalcone series was in silico screened for their ability to inhibit VEGFR-2 kinase. Further, in vitro research on HUVECs produced noteworthy inhibition by the chalcone hybrids. The highest activity was recognized by inhibitor 17 (Rizvi et ah, 2012).
Isoliquiritigenin (18), a natural product, has been identified as antiangio- genic candidate that mediates the activity inhibiting the VEGF expression. The natural chalcone exhibits HIF-la (hypoxia inducible factor-la) protea- some degradation in breast cancer cells and blocks the kinase activity via interaction with VEGFR-2 (Wang et ah, 2013b).
The strong VEGFR-2 inhibitory activity of 2,4-dihydroxy-6-methoxy- 3,5-dime thylchalcone (2) (Figure 11.4) remained the key highlights of Patent CN1454895A, which further depicts its utility in chemoprevention due to antiangiogenesis activity (Sun Yat-Sen Cancer Center, 2003).
FIGURE 11.4 Chalcones as VEGFR-2 inhibitors.
INHIBITION OF MATRIX METALLOPROTEINASES-2/9 BY CHALCONES
Matrix metalloproteinases (MMPs) are the enzyme class responsible for the degradation of small molecules present in the extracellular matrix (Genis et ah, 2006). Tissue inhibitors of metalloproteinases are known to inhibit MMP activity. MMP-2 and MMP-9 are the prime components responsible for the angiogenesis (Sang, 1998). MMP-9 has been seen to degrade the type-IV collagens present in the basement membrane, which leads to the clearance of matrix neighboring the endothelial cells. When the cryptic regulatory sequence gets exposed, it leads to proliferation and migration, which consequently leads to triggering of the angiogenic switch (Rundhaug, 2005). As the matrix-bound VEGF gets released by the cleavage process and the circulating endothelial precursor stem cells are released from bone marrow, the angiogenesis process initiates (Figure 11.5) (Stetler-Stevenson, 1999). A handful of molecules bearing chalcone pharmacophore have been preclinically perceived to block MMP-2 and MMP-9 very selectively and may be rationally designed in future for the complete blockade of angiogenic switching.
FIGURE 11.5 Illustration of the MMP-2/9 pathway.
Novel prenylated chalcones (19- and 20) obtained from the twigs of Dorstenia turbinate presented remarkable and complete inhibition of MMP-2 in brain tumor-derived glioblastoma cells. The authors also highlighted the importance of two prenylated groups in respective positions that play a dominant role in interaction with the MMP-2. The presence of free hydroxyl groups perceptibly unproved the inhibition of MMP-2 (Ngameni et al., 2006).
The wonder chalcone molecule isoliquiretigenin (18) has been seen to modulate a large number of biochemical targets. The compound of natural origin considerably reduces the VEGF expressions, MMP-2/9 expressions, and HIF-la levels in cancer cells and demonstrates antimigratory activities, which are the potential biomarkers for the antiangiogenic process. In addition to the above activities, the chalcone also inhibits phosphatidylinositol-3 kinase (PI3K) expression and p38 and Akt kinase phosphorylation and the suppression of NF-kp deoxyribonucleic acid (DNA)-binding activity (Wang et al., 2013a).
The antiangiogenic perspective of 4-maleamide peptidyl chalcones (21 and 22) in human prostate cancer cells (PC-3 and LNCaP) was studied by Rodrigues and co-workers where they observed alterations in the cell cycle, cellular invasion, changes in migration, anticlonogenic activity, and antiangiogenic potentials and marked MMP-9 inhibition in micromolar concentrations (Rodrigues et al., 2011).
The MMP inhibitory ability and TM4SF5 antagonistic activity of 4-(p-toluenesulfonylamino)-4'-hydroxy chalcone (TSAHC) (23) (Figure 11.6), a chalcone derivative, were profoundly studied, and its antiangiogenic behavior was established. The compound has been found to express antitumor activity in rats with no significant toxicity at a dose of 50 mg/kg (Park et al., 2012).
The antiangiogenic, antiproliferative, antimetastatic, and proapoptotic perspectives of garcinol (24), a chalcone-like compound isolated from Garcinia indica fruits, have been reported recently on pancreatic cancer cells. The polyisoprenylated benzophenone produces dose- and time-depen- dent induction of apoptosis (G0-G1 phase cell cycle arrest) in BxPC-3 and Panc-1 cell lines at 40 pM concentration. The compound expresses the activity by targeting transcription factor NF-kB, metastatic factors (PGE2, MMP-9, IL-8, and VEGF), and apoptotic factors (caspase-3/9, X-IAP, PARP, and cIAP), thereby preventing chemoresistance and neovascularization (Parasramka and Gupta, 2011). In addition to it, the molecule exhibit dose- dependent inhibition of cell invasion against pancreatic and prostate cancer cell lines by modulating a signal transducer and activator of the transcrip- tion-3 (STAT-3) signaling pathway (Ahmad et al., 2012).
The MMP inhibitory attributes (both collagenase and gelatinase subfamily) of 4'-hydroxy chalcone (6) and its derivatives as potential anticancer and chemo- preventive agents remained the center of attention of Ptent W02003037315A1. The antiangiogenic perspective of this compound continues to be the sole heart of this invention (Angiolab Inc., Assignee 2003).
FIGURE 11.6 Chalcones as MMP-2/9 inhibitors.
