Design, Synthesis And Biological Evaluation Of A Novel Bioactive Indane scaffold 2-(diphenylmethylene)c-2,3-dihydro-1H-inden-1-one with potential anticancer activity

Over the past decades, designing of privileged structures has emerged as a useful approach to the discovery and optimisation of novel biologically active molecules, and many have been successfully exploited across and within different target families. Examples include indole, quinolone, isoquinoline, benzofuran and chromone, etc. In the current study, we focus on synthesising a novel hybrid scaffold constituting naturally occurring benzophenone (14) and indanone (22) ring systems, leading to a general structure of 2-(diphenylmethylene)-2,3-dihydro-1H-inden-1-one (23). It was hypothesised this new hybrid system would provide enhanced anti-cancer activity owing to the presence of the common features associated with the tubulin binding small molecule indanocine (10) and the estrogen receptor (ER) antagonist tamoxifen (24). Key hybrid molecules were successfully synthesised and characterised, and the in vitro cytotoxicity assays were performed against cancer cell lines: MCF7 (breast) and SKBR3 (breast), DU145 (prostate) and A549 (lung). The methyl-, chloro- and methoxy-, para-substituted benzophenone hybrids displayed the greatest degree of cytotoxicity and the E-configuration derivatives 45, 47 and 49 being significantly most potent. We further verified that the second benzyl moiety of this novel hybrid scaffold is fundamental to enhance the cytotoxicity, especially in the SKBR3 (HER2+) by the E-methyl lead molecule 47, MCF7 (ER+) by 45 and 49, and A549 (NSCLC) cell lines by 49. These hybrid molecules also showed a significant accumulation of SKBR3 cells at S-phase of the cell cycle after 72 hrs, which demonstrates besides of being cytotoxic in vitro against SKBR3 cells, 47 disturbs the replication and development of this type of cancer causing a dose-dependent cell cycle arrest at S-phase. Our results suggest that DNA damage might be involved in the induction of SKBR3 cell death caused by the hybrid molecules, and therefore, this novel system may be an effective suppressor of HER2+/Neu-driven cancer growth and progression. The present study points to potential structural optimisation of the series and encourages further focussed investigation of analogues of this scaffold series toward their applications in cancer chemoprevention or chemotherapy

Privileged Structure: Novel Indane Scaffolds as Potential Anticancer and Anti-Inflammatory Agents

The identification and use of “privileged structures” can increase the reliability and shorten the process in the drug discovery and drug design (a-b). Indane scaffolds occur in various natural products and they constitute the privileged structure that is ubiquitous in many biologically and pharmaceutically active molecules (c-e). Our research group has been working on the synthesis and pharmacological activity of nature identical and synthetically modified indanes and indanones for 20 years. In the current study, the molecular design is centred on elaboration of a fern derived bioactive pharmacophore. The fern is used in traditional Taiwanese medicine to treat inflammation, allergy, stomach cramps and fever (f). Using a synthetic approach we have designed a novel chemical scaffold which can be modified to inhibit angiogenesis and 5-lipoxygenase activity. The parent scaffold and a number of strategically modified derivatives were initially screened using the Zebra fish (Danio rerio) model of tumour angiogenesis (g). This screen led to the identification of two lead molecules, which were then further evaluated in in vitro cell lines and colorectal explants. Results from these experiments establish that the lead compounds affect inter-segmental vessel formation. These molecules also inhibit cell invasion and tube formation. When evaluated in ex vivo colorectal cancer explants where the molecules significantly affected angiogenic and inflammatory protein secretions. These small molecules also alter gene expression. Modification of the scaffold can inhibit 5-lipoxygenase activity. These data suggest that the new scaffold may have significant potential in the treatment of angiogenesis and inflammatory related diseases

2-(Di­phenyl­methyl­idene)-2,3-di­hydro-1H-inden-1-one

In the title mol­ecule, C22H16O, the indanone ring system is approximately planar with a dihedral angle between the fused rings of 5.13 (14)°. Two benzene rings are linked together at one side of a double bond, sitting on either side of the indanone ring system and making dihedral angles of 70.30 (12) and 44.74 (13)° with it. In the crystal, hydrogen bonding is not present, but weak C—H⋯π or π–π inter­actions occur and mol­ecules form a sheet-like structure in the bc plane

2-(Diphenylmethylidene)-2,3-dihydro-1H-inden-1-one

In the title molecule, C22H16O, the indanone ring system is approximately planar with a dihedral angle between the fused rings of 5.13 (14)°. Two benzene rings are linked together at one side of a double bond, sitting on either side of the indanone ring system and making dihedral angles of 70.30 (12) and 44.74 (13)° with it. In the crystal, hydrogen bonding is not present, but weak C—H...π or π–π interactions occur and molecules form a sheet-like structure in the bc plane