title: Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification.
abstract: The spiro[pyrrolidine-3, 3´-oxindole] moiety is present as a core in number of alkaloids with substantial biological activities. Here in we report design and synthesis of a library of compounds bearing spiro[pyrrolidine-3, 3´-oxindole] motifs that demonstrated exceptional inhibitory activity against the proliferation of MCF-7 breast cancer cells. The synthesis involved a one pot Pictet Spengler-Oxidative ring contraction of tryptamine to the desired scaffolds and occurred in 1:1 THF and water with catalytic trifluoroacetic acid and stoichiometric N-bromosuccinimide as an oxidant. Phenotypic profiling indicated that these molecules induce apoptotic cell death in MCF-7 cells. Target deconvolution with most potent compound 5l from the library, using chemical proteomics indicated histone deacetylase 2 (HDAC2) and prohibitin 2 as the potential cellular binding partners. Molecular docking of 5l with HDAC2 provided insights pertinent to putative binding interactions.
authors: Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India.
authors: Santanu
authors: S
authors: Hati
authors: Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India.
authors: Sayantan
authors: S
authors: Tripathy
authors: Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India.
authors: Pratip Kumar
authors: PK
authors: Dutta
authors: Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India.
authors: Rahul
authors: R
authors: Agarwal
authors: Shantani Proteome Analytics Pvt. Ltd. 100 NCL Innovation Park, Dr. HomiBhabha Road, Pune - 411 008, India.
authors: Ramprasad
authors: R
authors: Srinivasan
authors: Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India.
authors: Ashutosh
authors: A
authors: Singh
authors: Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India.
authors: Shailja
authors: S
authors: Singh
authors: Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Buddha Nagar, 201314, Uttar Pradesh, India.
authors: Subhabrata
authors: S
authors: Sen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D049109:Cell Proliferation / Q000187:drug effects*; D002522:Chlorocebus aethiops; D015195:Drug Design; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry; D061986:MCF-7 Cells; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D000078183:Oxindoles; D011759:Pyrrolidines / Q000737:chemistry; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D011759:Pyrrolidines; D013141:Spiro Compounds; C022960:2-oxindole; C032519:pyrrolidine