Synthesis and evaluation of Strychnos alkaloids as MDR reversal agents for cancer cell eradication

Munagala, Surendrachary; Sirasani, Gopal; Kokkonda, Praveen; Phadke, Manali S.; Krynetskaia, Natalia F.; Lu, Peihua; Sharom, Frances J.; Chaudhury, Sidhartha; AbdulHameed, Mohamed Diwan M.; Tawa, Gregory J.; Wallqvist, Anders; Martinez, Rogelio L.; Childers, Wayne E.; Abou‐Gharbia, Magid; Krynetskiy, Evgeny; Andrade, Rodrigo

doi:10.1016/j.bmc.2013.12.022

Cited by 33 publications

(20 citation statements)

References 35 publications

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“…BCRP/MXR inhibitor 6‐prenylchrysin, a flavonoid compound, inhibits BCRP function by stimulating the ATPase activity of BCRP (Ahmed‐Belkacem et al, ). In addition, several MDR reversal agents show inhibition of PGP1 ATPase activity (Kopecka et al, ; Munagala et al, ). In general, some PGP1 inhibitors activate the ATPase of PGP1, whereas others may reduce it.…”

Section: Discussionmentioning

confidence: 99%

NVP‐TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P‐glycoprotein (PGP1) function

Zhang

Shen

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEIncreased expression of P-glycoprotein (PGP1) is one of the major causes of multidrug resistance (MDR) in cancer, including in osteosarcoma, which eventually leads to the failure of cancer chemotherapy. Thus, there is an urgent need to develop effective therapeutic strategies to override the expression and function of PGP1 to counter MDR in cancer patients. EXPERIMENTAL APPROACHIn an effort to search for new chemical entities targeting PGP1-associated MDR in osteosarcoma, we screened a 500+ compound library of known kinase inhibitors with established kinase selectivity profiles. We aimed to discover potential drug synergistic effects among kinase inhibitors and general chemotherapeutics by combining inhibitors with chemotherapy drugs such as doxorubicin and paclitaxel. The human osteosarcoma MDR cell lines U2OSR2 and KHOSR2 were used for the initial screen and secondary mechanistic studies. KEY RESULTSAfter screening 500+ kinase inhibitors, we identified NVP-TAE684 as the most effective MDR reversing agent. NVP-TAE684 significantly reversed chemoresistance when used in combination with doxorubicin, paclitaxel, docetaxel, vincristine, ET-743 or mitoxantrone. NVP-TAE684 itself is not a PGP1 substrate competitive inhibitor, but it can increase the intracellular accumulation of PGP1 substrates in PGP1-overexpressing cell lines. NVP-TAE684 was found to inhibit the function of PGP1 by stimulating PGP1 ATPase activity, a phenomenon reported for other PGP1 inhibitors.

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Section: Discussionmentioning

confidence: 99%

NVP‐TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P‐glycoprotein (PGP1) function

Zhang

Shen

et al. 2016

British J Pharmacology

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“…Tariquidar (XR9576) in particular is a non-competitive P-gp inhibitor with greater affinity for P-gp than its substrates (20). Finally, fourth-generation P-gp inhibitors (e.g., the cyclic peptide QZ59SE and the natural compounds lamellarin and gomisin A) display low toxicity but high selectivity and potency are currently under development and evaluated for their use in humans (158, 159). MRP inhibitors include probenecid, MK-571, and LY402913 (2).…”

Section: Potential Mechanisms Of Asd Resistancementioning

confidence: 99%

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

2017

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Epilepsy is a common neurological disorder that affects over 70 million people worldwide. Despite the recent introduction of new antiseizure drugs (ASDs), about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Early identification of patients who will become refractory to ASDs could help direct such patients to appropriate non-pharmacological treatment, but the complexity in the temporal patterns of epilepsy could make such identification difficult. The target hypothesis and transporter hypothesis are the most cited theories trying to explain refractory epilepsy, but neither theory alone fully explains the neurobiological basis of pharmacoresistance. This review summarizes evidence for and against several major theories, including the pharmacokinetic hypothesis, neural network hypothesis, intrinsic severity hypothesis, gene variant hypothesis, target hypothesis, and transporter hypothesis. The discussion is mainly focused on the transporter hypothesis, where clinical and experimental data are discussed on multidrug transporter overexpression, substrate profiles of ASDs, mechanism of transporter upregulation, polymorphisms of transporters, and the use of transporter inhibitors. Finally, future perspectives are presented for the improvement of current hypotheses and the development of treatment strategies as guided by the current understanding of refractory epilepsy.

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“…Heck cyclization of 12 using Pd(OAc) 2 , PPh 3 , and Et 3 N, which was inspired by Rawal’s elegant approach to the Strychnos alkaloids, 35 accessed the D-ring to deliver (−)-akuammicine ( 1 ) in 87% yield (10% overall yield in nine steps). 29 …”

Section: Resultsmentioning

confidence: 99%

“…Compounds 1 and 7 – 12 were prepared according to the procedures of Andrade. 29 ( Z )-2-Iodobutenyl bromide was prepared according to the procedure of Cook. 36 For cross-metathesis reactions, CH 2 Cl 2 was deaerated by bubbling argon (1 min/mL).…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Pentacyclic Strychnos Alkaloids as Selective Modulators of the ABCC10 (MRP7) Efflux Pump

et al. 2014

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The selective modulation of ABC efflux pumps overexpressed in multidrug resistant cancers (MDR) and attendant resensitization to chemotherapeutic agents represents a promising strategy for treating cancer. We have synthesized four novel pentacyclic Strychnos alkaloids alstolucines B (2), F (3), A (5), and N-demethylalstogucine (4), in addition to known Strychnos alkaloid echitamidine (16), and evaluated compounds 1–3, 5 in biochemical assays with ABCC10 and P-gp. Alstolucines B (2) and F (3) inhibited ABCC10 ATPase activity at 12.5 μM without affecting P-gp function; moreover, they resensitized ABCC10-transfected cell lines to paclitaxel at 10 μM. Altogether, the alstolucines represent promising lead candidates in the development of modulators of ABCC10 for MDR cancers overexpressing this pump.

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Synthesis and evaluation of Strychnos alkaloids as MDR reversal agents for cancer cell eradication

Cited by 33 publications

References 35 publications

NVP‐TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P‐glycoprotein (PGP1) function

NVP‐TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P‐glycoprotein (PGP1) function

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

Synthesis and Biological Evaluation of Pentacyclic Strychnos Alkaloids as Selective Modulators of the ABCC10 (MRP7) Efflux Pump

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