Part 3. A Novel Stereocontrolled, In Situ, Solution- and Solid-Phase, Aza Michael Approach for High-Throughput Generation of Tetrahydroaminoquinoline-Derived Natural-Product-like Architectures

With the goal of rapidly accessing tetrahydroquinoline-based natural-product-like polycyclic architectures, herein, we report an unprecedented, in situ, stereocontrolled Aza Michael approach in solution and on the solid phase. The mild reaction conditions required to reach the desired target are highly attractive for the use of this method in library generation. To our knowledge, this approach has not been used before, and it opens a novel route leading to a wide variety of tetrahydroquinoline-derived bridged tricyclic derivatives.NRC publication: Ye

PI3K/AKT/mTOR inhibition in combination with doxorubicin is an effective therapy for leiomyosarcoma.

BackgroundLeiomyosarcoma (LMS) is a common type of soft tissue sarcoma that responds poorly to standard chemotherapy. Thus the goal of this study was to identify novel selective therapies that may be effective in leiomyosarcoma by screening cell lines with a small molecule library comprised of 480 kinase inhibitors to functionally determine which signalling pathways may be critical for LMS growth.MethodsLMS cell lines were screened with the OICR kinase library and a cell viability assay was used to identify potentially effective compounds. The top 10 % of hits underwent secondary validation to determine their EC50 and immunoblots were performed to confirm selective drug action. The efficacy of combination drug therapy with doxorubicin (Dox) in vitro was analyzed using the Calcusyn program after treatment with one of three dosing schedules: concurrent treatment, initial treatment with a selective compound followed by Dox, or initial treatment with Dox followed by the selective compound. Single and combination drug therapy were then validated in vivo using LMS xenografts.ResultsCompounds that targeted PI3K/AKT/mTOR pathways (52 %) were most effective. EC50s were determined to validate these initial hits, and of the 11 confirmed hits, 10 targeted PI3K and/or mTOR pathways with EC50 values <1 μM. We therefore examined if BEZ235 and BKM120, two selective compounds in these pathways, would inhibit leiomyosarcoma growth in vitro. Immunoblots confirmed on-target effects of these compounds in the PI3K and/or mTOR pathways. We next investigated if there was synergy with these agents and first line chemotherapy doxorubicin (Dox), which would allow for earlier introduction into patient care. Only combined treatment of BEZ235 and Dox was synergistic in vitro. To validate these findings in pre-clinical models, leiomyosarcoma xenografts were treated with single agent and combination therapy. BEZ235 treated xenografts (n = 8) demonstrated a decrease in tumor volume of 42 % whereas combining BEZ235 with Dox (n = 8) decreased tumor volume 68 % compared to vehicle alone.ConclusionsIn summary, this study supports further investigation into the use of PI3K and mTOR inhibitors alone and in combination with standard treatment in leiomyosarcoma patients

Part 1. Modular Approach to Obtaining Diverse Tetrahydroquinoline-Derived Polycyclic Skeletons for Use in High-Throughput Generation of Natural-Product-like Chemical Probes

A practical synthesis of a tetrahydroaminoquinoline scaffold (12) was developed that used a stereocontrolled aza Michael as the key reaction. Three tetrahydroquinoline alkaloid-like, tricyclic derivatives 16, 18, and 19 with different medium to macrocyclic ring skeletons were obtained, using this scaffold as the starting material, in a modular manner. The macrocyclic compounds with an isolated olefin and an electron-deficient olefin were obtained by ring-closing metathesis approaches. Compounds 16 and 18 are unique and contain bridged 10- and 12-membered functionalized rings. The NMR studies of these compounds revealed interesting information on the conformation of the bicyclic scaffolds that was dependent on the nature and the size of the macrocyclic rings. Finally, this modular methodology, using compound 21 anchored onto the solid support, successfully led to the generation of different macrocyclic derivatives, 23, 25, and 27 in solid-phase synthesis. The solid-phase synthesis approach outlined in this article has the potential to generate tetrahydroquinolinebased tricyclic compounds containing different medium to macrocyclic architectures.NRC publication: Ye

Reagent-based, modular, tandem Michael approach for obtaining different indoline alkaloid-inspired polycyclic architectures

A modular, reagent-based approach to obtain different indoline alkaloid-inspired, tetracyclic architectures is developed. With the use of TBSOTf as a Lewis acid, we report here a tandem Michael-based approach that led to the synthesis of a diastereomeric mixture of tetracyclic derivatives with two additional six-membered rings. By simply changing the Lewis acid to TMSOTf, we were able to obtain a different tetracyclic compound having additional functionalized 5- and 7-membered rings with complete stereocontrol.NRC publication: Ye

The discovery of small molecule chemical probes of Bcl-XL and Mcl-1

A tetrahydroaminoquinoline-based library was generated with the goals of finding small molecule modulators of protein-protein interactions. Several library members as well as other related intermediates were tested for their ability to bind to Bcl-XL and Mcl-1 by in silico and 15N NMR studies. The NMR study led to the identification of the tetrahydroaminoquinoline-based nude scaffold, 7 as a weak binder (Kd?=?200?[mu]M for Bcl-XL and Kd?=?300?[mu]M for Mcl-1) to both proteins. Using this scaffold as the starting material, we then synthesized a focused library of only 9 derivatives by applying the principles of a fragment-based approach. All these derivatives were then tested by NMR and this led to the discovery of a novel, small molecule (MIPRALDEN, 17) as a binder to Mcl-1 and Bcl-XL (KD?=?25 and 70?[mu]M). This finding is novel because to our knowledge there are not many small molecules known in the literature that bind to Mcl-1.NRC publication: Ye

One-Pot Construction of Isoindolo[2,1-a]quinoline System

Polycyclic compounds bearing isoindolo[2,1-a]quinoline system were easily prepared stereo- and regioselectively, and in one-pot, in a tandem fashion containing Povarov\u2019s multicomponent and condensation reactions. Involving a stepwise route for the aza Diels\u2013Alder reaction within the synthesis was suggested.Peer reviewed: YesNRC publication: Ye

Advances in solution- and solid-phase synthesis toward the generation of natural product-like libraries

NRC publication: Ye