Synthesis of novel pyranochromanone amide hybrids, by combining pyranochromanone pharmacophore and privileged scaffolds such as 2-amino-1,3,4-thiadiaole/2-aminothiazole/aminopyridine/aminonaphthalene and anti-cancer evaluation of a series led us to discover a series of new chemical entities (NCEs) showing broad spectrum of anti-cancer activity against three different human cancer cell lines (MCF-7, A549 and HeLa), at IC50 values ranging from 14.3 to 97.8 μM. Among them, some compounds such as 15b, 15d, 20a and 20b displayed excellent activity against breast cancer cell line MCF-7. Detailed biological studies such as AO/EB dual staining, Hoechst 33342 staining, FACS analysis of mitochondrial membrane potential (Δψm) using JC-1 dye and DNA fragmentation confirmed the apoptosis induced by the hybrids. Gene expression studies by Real time RT-PCR has shown that these compounds are efficient regulator of anti-apoptotic gene Bcl-2. Western blot analysis also revealed that these compounds persuade apoptosis through intrinsic pathway by up-regulating the pro-apoptotic protein Bax and down-regulating the anti-apoptotic protein Bcl-2. Molecular docking studies reveal that compounds 15b and 20b binds efficiently with Bcl-2 promoter G-quadruplex.