Ramesh Samineni

Versatile Route to Benzoannulated Medium-Ring Carbocycles via Aryne Insertion into Cyclic 1,3-Diketones: Application to a Synthesis of Radermachol

A general approach involving the insertion of in situ generated aryne into the C-C bond of cyclic 1,3-diketones for rapidly assembling functionalized benzo-fused medium ring carbocycles is delineated. The efficacy of the methodology has been demonstrated through a concise total synthesis of pentacyclic natural product radermachol.

A novel natural product inspired scaffold with robust neurotrophic, neurogenic and neuroprotective action

In search for drugs to treat neuropsychiatric disorders wherein neurotrophic and neurogenic properties are affected, two neurotrophically active small molecules specially crafted following natural product leads based on 2-oxa-spiro[5.5]-undecane scaffold, have been thoroughly evaluated for their neurotrophic, neurogenic and neuroprotective potential in ex vivo primary culture and in vivo zebrafish and mouse models. The outcome of in vivo investigations suggest that one of these molecules is more neurotrophic than neurogenic while the other one is more neurogenic than neurotrophic and the former exhibits remarkable neuroprotection in a mouse acute ischemic stroke model. The molecular mechanisms of action of these compounds appear to be through the TrkB-MEK-ERK-CREB-BDNF pathway as pre-treatment with neurotrophin receptor TrkB inhibitor ANA-12 and MEK inhibitor PD98059 attenuates the neurotrophic action of compounds.

A 2-oxa-spiro[5.4]decane scaffold displays neurotrophic, neurogenic and anti-neuroinflammatory activities with high potential for development as a versatile CNS therapeutic

Following our recent discovery of a new scaffold exhibiting significant neurotrophic and neurogenic activities, a structurally tweaked analogue, embodying a 2-oxa-spiro [5.4]decane framework, has been conceptualised and found to be more potent and versatile. It exhibits enhanced neurotrophic and neurogenic action in in vitro, ex vivo and in vivo models and also shows robust neuroprotection in mouse acute cerebral stroke model. The observed attributes are traceable to the predominant activation of the TrkB-PI3K-AKT-CREB pathway. In addition, it also exhibits remarkable anti-neuroinflammatory activity by concurrently down-regulating pro-inflammatory cytokines IL-1α and IL-6, thereby providing a unique molecule with a trinity of neuroactivities, i.e. neurotrophic, neurogenic and anti-inflammatory. The new chemical entity disclosed here has the potential to be advanced as a versatile therapeutic molecule to treat stroke, depression, and possibly other neuropsychiatric disorders associated with attenuated neurotrophic/ neurogenic activity, together with heightened neuroinflammation.

Stitching Oxindoles and Ynones in a Domino Process: Access to Spirooxindoles and Application to a Short Synthesis of Spindomycin B

A general, transition-metal-free, one-pot, domino Michael-SNAr or AdNE substitution protocol was devised for spiroannulation of oxindoles with ortho-bromoaryl ynones, β-bromoalkenyl ynones, and β-bromoalkenyl enones in a convenient and efficient manner. As an application, a short synthesis of tetracyclic alkaloid spindomycin B was accomplished.