Synthesis of C-1 indol-3-yl substituted tetrahydroisoquinoline derivatives via a Pictet–Spengler approach

Larsson, Rikard; Blanco, Narda; Johansson, Martin; Sterner, Olov

doi:10.1016/j.tetlet.2012.07.017

Cited by 12 publications

(12 citation statements)

References 14 publications

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“…ISA-2011B, a diketopiperazine fused C-1 indol-3-yl substituted 1,2,3,4-tetrahydroisoquinoline derivative, was discovered as a result of our development of C-1 indol-3-yl substituted 1,2,3,4-tetrahydroisoquinolies via a Pictet-Spengler approach (32) (Fig. 1A) and was found to have a potent inhibitory effect on proliferation in various types of aggressive cancer cell lines (Fig.…”

Section: Resultsmentioning

confidence: 99%

The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer

Semenas

Hedblom

Miftakhova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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130

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Significance Prostate cancer is the most common malignancy and the third leading cancer-related cause of death among men of the Western world. Treatment options at advanced stages of the disease are scarce, and better therapies are in urgent need. In our study, we show that the clinically relevant lipid kinase phosphatidylinositol-4-phosphate 5-kinase-α (PIP5Kα) plays an important role in cancer cell invasion and survival by regulating the PI3K/AKT/androgen receptor pathways. Elevated levels of PIP5K1α contribute to cancer cell proliferation, survival, and invasion. In this context we introduce a newly developed compound, ISA-2011B, with promising anticancer effects by inhibiting the PIP5K1α-associated AKT pathways. Conclusively, we propose that PIP5K1α may be used as a potential therapeutic target for treatment of advanced prostate cancer.

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Section: Resultsmentioning

confidence: 99%

The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer

Semenas

Hedblom

Miftakhova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

130

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“…Phenanthroindolizidines (50 [71,72]), phenanthroquinolizidines (51 [72]), tetrahydroprotoberberines (53 [67,68]), pyrroloisoquinolines (55 [69,70]), and diketopiperazine-fused THIQs (65 [73], vide infra) embody the tetrahydroisoquinoline skeleton, while indolizinoindoles (57 [74,75]), THBC-imidazolinediones (59 [76]), THBC-piperazinedione (61 [77,78]), the tetracyclic indole alkaloids (S)-harmicine (pyrrole-fused THBC, [66,79]), and (S)-eleagnine (1-methyl THBC, [66,80] represent the THBC-containing polyheterocycles. The additional ring can be already present in the imine substrate before the P-S reaction (type A) or can be built on the THIQ/THBC skeleton exploiting the functionality of some substituents (type B).…”

Section: Polyheterocyclesmentioning

confidence: 99%

“…Conversely, 13a-methylphenanthroindolizidine (n=1) 50c (R 1 = OMe, R 2 = R = H; Scheme 13) was obtained by an enantioselective approach, including inter alia, an efficient stereoselective Seebach's alkylation and P-S cyclization [72]. The additional ring can be an aromatic ring as in protoberberines 53 [67,68], a pyrrole nucleus as in pyrroloisoquinolines (55 [69,70]) and phenanthroindolizidines (50 [71,72]), a piperazine or a diketopiperazine fused ring, as in phenathroquinolizidines 51 [72] and THIQ analogs 65 [73].…”

Section: Polyheterocyclesmentioning

confidence: 99%

“…Following a Type-A procedure, the THIQ products 65a can be in turn transformed into optically active diketopiperazine fused analogue 66a. Alternatively, compounds 66b were directly prepared drom L-DOPA derivative 63b by condensation with N-Boc protected 1H-indole-3-carbaldehydes 64b without isolation of the P-S precursors 65b (Scheme 17) [73]. The type C procedure foresees two simultaneous ring closures, as in the enantiospecific and stereo-selective P-S bis-cyclization between (R)-(−)-methyl-2-amino-3-(3,4-dimethoxyphenylpropanoate 67 and 4-chloro-1,1-dimethoxybutane 68 preferentially, which provided the cis-tricyclic The type C procedure foresees two simultaneous ring closures, as in the enantiospecific and stereo-selective P-S bis-cyclization between (R)-(−)-methyl-2-amino-3-(3,4-dimethoxyphenyl-propanoate 67 and 4-chloro-1,1-dimethoxybutane 68 preferentially, which provided the cis-tricyclic adduct 69 precursor of the natural product (+)-crispine A (Scheme 18).…”

Section: Polyheterocyclesmentioning

confidence: 99%

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The Pictet-Spengler Reaction Updates Its Habits

et al. 2020

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The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011–2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations.

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“…Up to now, only one inhibitor of hPIP5K1a, namely ISA-2011B, is known [10]. ISA-2011B belongs to C-1 indol-3-yl substituted tetrahydroisoquinolines [21]. In order to comply with the apparent demand for new hPIP5K1a inhibitors, we developed the first in vitro screening procedure for the identification of hPIP5K1a kinase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Development of an in vitro screening assay for PIP5K1α lipid kinase and identification of potent inhibitors

et al. 2020

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AbbreviationsAKT, protein kinase B; AR, androgen receptor; CRPC, castration-resistant prostate cancer; LIF, laser-induced fluorescence; MOPS, 3-(Nmorpholino)propane sulfonic acid; mTOR, mammalian target of rapamycin; PARP, poly(ADP-ribose) polymerase; PCa, prostate cancer; PI(4) P, phosphatidylinositol-4-phosphate; PIP 2 , phosphatidylinositol-4,5-bisphosphate; PIP5K1a, phosphatidylinositol-4-phosphate-5-kinase type 1a; PTEN, phosphatase and tensin homolog; TSP, Tris/sodium deoxycholate/1-propanol.Inhibition of PIP5K1a by pyranobenzoquinones K. Str€ atker et al.

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Synthesis of C-1 indol-3-yl substituted tetrahydroisoquinoline derivatives via a Pictet–Spengler approach

Cited by 12 publications

References 14 publications

The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer

The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer

The Pictet-Spengler Reaction Updates Its Habits

Development of an in vitro screening assay for PIP5K1α lipid kinase and identification of potent inhibitors

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