A Practical and Efficient Synthesis of Thalidomide via Na/Liquid NH<sub>3</sub> Methodology<sup>1</sup>

Varala, Ravi; Adapa, Srinivas R.

doi:10.1021/op050129z

Cited by 24 publications

(16 citation statements)

References 27 publications

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“…The organic layer was washed with H 2 O, followed by brine, dried over Na 2 SO 4 and filtered. After evaporation of the solvent, the desired d -glutamic acid dimethyl ester was obtained as a yellowish oil (0.315 g, 1.79 mmol, 87% yield) [ 47 ]. NMR spectrum was measured on a 400 MHz Avance 4 Neo (Bruker) spectrometer.…”

Section: Methodsmentioning

confidence: 99%

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177

et al. 2020

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Targeting of cholecystokinin-2 receptor (CCK2R) expressing tumors using radiolabeled minigastrin (MG) analogs is hampered by rapid digestion of the linear peptide in vivo. In this study, a new MG analog stabilized against enzymatic degradation was investigated in preclinical studies to characterize the metabolites formed in vivo. The new MG analog DOTA-DGlu-Pro-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH2 comprising site-specific amino acid substitutions in position 2, 6 and 8 and different possible metabolites thereof were synthesized. The receptor interaction of the peptide and selected metabolites was evaluated in a CCK2R-expressing cell line. The enzymatic stability of the 177Lu-labeled peptide analog was evaluated in vitro in different media as well as in BALB/c mice up to 1 h after injection and the metabolites were identified based on radio-HPLC analysis. The new radiopeptide showed a highly increased stability in vivo with >56% intact radiopeptide in the blood of BALB/c mice 1 h after injection. High CCK2R affinity and cell uptake was confirmed only for the intact peptide, whereas enzymatic cleavage within the receptor specific C-terminal amino acid sequence resulted in complete loss of affinity and cell uptake. A favorable biodistribution profile was observed in BALB/c mice with low background activity, preferential renal excretion and prolonged uptake in CCK2R-expressing tissues. The novel stabilized MG analog shows high potential for diagnostic and therapeutic use. The radiometabolites characterized give new insights into the enzymatic degradation in vivo.

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Section: Methodsmentioning

confidence: 99%

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177

et al. 2020

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“…The glutarimide subunit can be incorporated into 4-fluorothalidomide ( 5 ) by using compound 2 , which can be formed easily by converting Boc-Gln-OH ( 1 ) into 2 via an intramolecular coupling ( Scheme 1 , steps a-b) ( Steinebach et al, 2018 ). Another option to afford the desired precursor 2 over three steps with a 57% yield was presented where l -glutamine was used as starting material ( Varala and Adapa, 2005 ). Alternatively, 3-aminopiperidine-2,6-dione hydrochloride can be used in place of 2 ( Zhou et al, 2018 ; An et al, 2019 ).…”

Section: E3 Ligasesmentioning

confidence: 99%

E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points

et al. 2021

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Proteolysis-targeting chimeras (PROTACs) have received tremendous attention as a new and exciting class of therapeutic agents that promise to significantly impact drug discovery. These bifunctional molecules consist of a target binding unit, a linker, and an E3 ligase binding moiety. The chemically-induced formation of ternary complexes leads to ubiquitination and proteasomal degradation of target proteins. Among the plethora of E3 ligases, only a few have been utilized for the novel PROTAC technology. However, extensive knowledge on the preparation of E3 ligands and their utilization for PROTACs has already been acquired. This review provides an in-depth analysis of synthetic entries to functionalized ligands for the most relevant E3 ligase ligands, i.e. CRBN, VHL, IAP, and MDM2. Less commonly used E3 ligase and their ligands are also presented. We compare different preparative routes to E3 ligands with respect to feasibility and productivity. A particular focus was set on the chemistry of the linker attachment by discussing the synthetic opportunities to connect the E3 ligand at an appropriate exit vector with a linker to assemble the final PROTAC. This comprehensive review includes many facets involved in the synthesis of such complex molecules and is expected to serve as a compendium to support future synthetic attempts towards PROTACs.

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“…This indicated the possibility of easy synthesis of α-amino glutarimide simply by autoclaving aqueous solutions of L-glutamine for 40 min. It would be pertinent to mention that in general, the synthesis of the glutarimide ring requires a minimum of 2-3 step reactions [ 8 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Many glutarimide derivatives are partial agonists of the central nervous system (CNS) and their actions range from convulsive and analeptic (agonist) to anticonvulsive and hypnotic (antagonist). The importance of glutarimide moeties in antibiotics such as the cycloheximides is well known and they act by inhibiting the synthesis of bacterial peptides at the initiation and extension steps [ 8 ]. However, the present study elucidates and reports a new function of α-amino glutarimide as a potent facilitator of Agrobacterium infection of generally resistant host plants.…”

Section: Introductionmentioning

confidence: 99%

Chemical modification of L-glutamine to alpha-amino glutarimide on autoclaving facilitates Agrobacterium infection of host and non-host plants: A new use of a known compound

et al. 2011

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BackgroundAccidental autoclaving of L-glutamine was found to facilitate the Agrobacterium infection of a non host plant like tea in an earlier study. In the present communication, we elucidate the structural changes in L-glutamine due to autoclaving and also confirm the role of heat transformed L-glutamine in Agrobacterium mediated genetic transformation of host/non host plants.ResultsWhen autoclaved at 121°C and 15 psi for 20 or 40 min, L-glutamine was structurally modified into 5-oxo proline and 3-amino glutarimide (α-amino glutarimide), respectively. Of the two autoclaved products, only α-amino glutarimide facilitated Agrobacterium infection of a number of resistant to susceptible plants. However, the compound did not have any vir gene inducing property.ConclusionsWe report a one pot autoclave process for the synthesis of 5-oxo proline and α-amino glutarimide from L-glutamine. Xenobiotic detoxifying property of α-amino glutarimide is also proposed.

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A Practical and Efficient Synthesis of Thalidomide via Na/Liquid NH₃ Methodology¹

Cited by 24 publications

References 27 publications

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177

E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points

Chemical modification of L-glutamine to alpha-amino glutarimide on autoclaving facilitates Agrobacterium infection of host and non-host plants: A new use of a known compound

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A Practical and Efficient Synthesis of Thalidomide via Na/Liquid NH3 Methodology1

Cited by 24 publications

References 27 publications

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177

E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points

Chemical modification of L-glutamine to alpha-amino glutarimide on autoclaving facilitates Agrobacterium infection of host and non-host plants: A new use of a known compound

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A Practical and Efficient Synthesis of Thalidomide via Na/Liquid NH₃ Methodology¹