Synthesis of novel deuterium labelled derivatives of N-alkylated polyamines

Keinänen, Tuomo A.; Khomutov, Alex R.; Auriola, Seppo; Weisell, Janne; Alhonen, Leena; Jänne, Juhani; Vepsäläinen, Jouko

doi:10.1016/j.tet.2008.10.071

Cited by 13 publications

(12 citation statements)

References 52 publications

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“…Butane-1,4-diamine dihydrochloride (PUT, 98%), N 1 -(3-aminopropyl)butane-1,4-diamine trihydrochloride (SPD, 98%), N,N’ -bis-(3-aminopropyl)butane-1,4-diamine tetrahydro-chloride (SPM, >95%) were from Sigma. All the deuterated reference compounds except those described below were prepared as previously described (Häkkinen et al 2009). Benzylamine hydrochloride (BnNH 2 ) was prepared from benzylamine and recrystallized from ethanol-ethyl acetate.…”

Section: Methodsmentioning

confidence: 99%

“…α,α- 2 H 2 -Benzylamine hydrochloride (BnNH 2 -2D) was prepared from benzonitrile (1 g, 9.7 mmol) and LiAlD 4 (815 mg, 19.4 mmol) using the previously described methods (Häkkinen et al 2009) to give BnNH 2 -2D as colourless crystals. (974 mg, 69 %).…”

Section: Methodsmentioning

confidence: 99%

“…N 1 -(3-Benzylamino-1,1,2,2- 2 H 4 -propyl)butane-1,4-diamine trihydrochloride (BnSPD-4D) was prepared from N 1 -benzyl-bis- N 1 , N 3 -(2-nitrobenzenesulfonyl)-2,2,3,3- 2 H 4 -propane-1,3-diamine as described in (Häkkinen et al 2009) (808 mg, 1.5 mmol) and N -(4-iodobutyl)phthalimide (Järvinen et al 2006b) (545 mg, 1.65 mmol) using method described in (Häkkinen et al 2009) to give BnSPD-4D (193 mg, 37 %) as a colourless solid. 1 H NMR (D 2 O): δ 7.55-7.48 (5H, m), 4.29 (2H, s), 3.20 (2H, s), 3.16-3.10 (2H, m), 3.10-3.03 (2H, m), 1.85-1.73 (4H, m); 13 C NMR (D 2 O): δ 133.3, 132.7 (2C), 132.6, 132.2 (2C), 54.1, 49.8, 46.6 (2C, s + m), 41.7, 26.7, 25.6, 24.7 (quintet, J = 20 Hz).…”

Section: Methodsmentioning

confidence: 99%

“…N,N ′-bis-(3-Benzylaminopropyl)butane-1,4-diamine tetrahydrochloride ( DBSPM ) was prepared from N 1 -benzyl-bis- N 1 , N 3 -(2-nitro-benzenesulfonyl)propane-1,3-diamine (Häkkinen et al 2009) (1 g, 1.87 mmol) and 1,4-diiodobutane (276 mg, 0.89 mmol) using methods described in (Häkkinen et al 2009) to give DBSPM (211 mg, 45 %) as a colourless solid. 1 H NMR chemical shifts as described earlier (Bergeron et al 2001); 13 C NMR (D 2 O): δ 133.4 (2C), 132.8 (4C), 132.7 (2C), 132.2 (4C), 54.1 (2C), 49.9 (2C), 47.4 (2C), 46.8 (2C), 25.6 (2C), 25.5 (2C).…”

Section: Methodsmentioning

confidence: 99%

“…Data acquisition and analysis were performed using an Agilent MassHunter Workstation software (Agilent Corporation, MA, USA). 1 H and 13 C NMR spectra were measured on a Bruker Avance (Bruker, Rheinstetter, Germany) 500 DRX spectrometer as described earlier (Häkkinen et al 2009). …”

Section: Methodsmentioning

confidence: 99%

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Metabolism of N-alkylated spermine analogues by polyamine and spermine oxidases

et al. 2009

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SUMMARYN-alkylated polyamine analogues have potential as anticancer and antiparasitic drugs. However, their metabolism in the host has remained incompletely defined thus potentially limiting their utility. Here, we have studied the degradation of three different spermine analogues N, N′-bis-(3-ethylaminopropyl)butane-1,4-diamine (DESPM), N-(3-benzyl-aminopropyl)-N'-(3-ethylaminopropyl)butane-1,4-diamine (BnEtSPM) and N,N′-bis-(3-benzylaminopropyl)butane-1,4-diamine (DBSPM) and related mono-alkylated derivatives as substrates of recombinant human polyamine oxidase (APAO) and spermine oxidase (SMO). APAO and SMO metabolized DESPM to EtSPD (K m(APAO) =10μM, k cat(APAO) =1.1s −1 and K m(SMO) =28μM, k cat(SMO) =0.8s −1 , respectively), metabolized BnEtSPM to EtSPD (K m(APAO) =0.9 μM, k cat(APAO) =1.1s −1 and K m(SMO) =51μM, k cat(SMO) =0.4s −1 , respectively), and metabolized DBSPM to BnSPD (K m(APAO) =5.4μM, k cat(APAO) = 2.0s −1 and K m(SMO) =33μM, k cat(SMO) =0.3s −1 , respectively). Interestingly, mono-alkylated spermine derivatives were metabolized by APAO and SMO to SPD (EtSPM K m(APAO) =16μM, k cat(APAO) =1.5s −1 ; K m(SMO) =25μM, k cat(SMO) =8.2s −1 ; BnSPM K m(APAO) =6.0μM, k cat(APAO) =2.8s −1 ; K m(SMO) =19μM, k cat(SMO) =0.8s −1 , respectively). Surprisingly, E t S P D ( K m(APAO) =37μM, k cat(APAO) =0.1s −1 ; K m(SMO) =48μM, k cat(SMO) =0.05s −1 ) and BnSPD (K m(APAO) =2.5μM, k cat(APAO) =3.5s −1 ; K m(SMO) =60μM, k cat(SMO) =0.54s −1 ) were metabolized to SPD by both the oxidases. Furthermore, we studied the degradation of DESPM, BnEtSPM or DBSPM in the DU145 prostate carcinoma cell line. The same major metabolites EtSPD and/or BnSPD were detected both in the culture medium and intracellularly after 48 hours of culture. Moreover, EtSPM and BnSPM were detected from cell samples. Present data shows that inducible SMO parallel with APAO could play an important role in polyamine based drug action, i.e. degradation of parent drug and its metabolites, having significant impact on efficiency of these drugs, and hence for the development of novel N-alkylated polyamine analogues.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Metabolism of N-alkylated spermine analogues by polyamine and spermine oxidases

et al. 2009

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Enantioselective synthesis of cyclic and linear diamines by imine cycloadditions

2020

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Imine is one of the most versatile functional groups in chemistry and biochemistry fields. Although many biochemical reactions involve imine formation, the inherently unstable property of N‐alkyl‐α,β‐unsaturated imines still hindered their utilization in organic synthesis. In this article, we described that the N‐alkyl‐α,β‐unsaturated imines, which prepared from alkylamines and acrolein, could smoothly react through [4 + 4] cycloaddition to give eight‐membered diazacyclooctane derivatives in excellent yields. Under a similar condition, in the presence of formaldehyde, the [4 + 2] and [4 + 2 + 2] cycloadditions could lead to the formation of six‐membered hexahydropyrimidine or eight‐membered triazacyclooctanes, depending on the substituent of aldehydes. Moreover, an easy functional group manipulation of the cyclic products obtained from these cycloadditions can provide variously substituted chiral linear diamines. We can utilize these novel reactivities to reveal the unknown and essential properties of many biological processes that involve N‐alkyl‐unsaturated imines.

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A new liquid chromatography/electrospray ionization mass spectrometry method for the analysis of underivatized aliphatic long‐chain polyamines: application to diatom‐rich sediments

Bridoux

Annenkov

Menzel

et al. 2011

Rapid Comm Mass Spectrometry

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Natural polyamines are found in all three domains of life and long-chain polyamines (LCPAs) play a special role in silicifying organisms such as diatoms and sponges where they are actively involved in the complex formation and nanopatterning of siliceous structures. With chain lengths extending up to 20 N-methylated propylamine repeat units, diatom LCPAs constitute the longest natural polyamines. Mixtures of natural LCPAs are typically purified in bulk using ion-exchange, size-exclusion and dialysis and then analyzed either by direct infusion mass spectrometry or by MALDI-TOF. Here, we describe a novel ion-pairing liquid chromatographic method that allows baseline separation, detection and structural elucidation of underivatized aliphatic methylated and non-methylated LCPAs with a wide range of chain lengths. Complete separation of synthetic mixtures of LCPA species differing by either a propylamine or an N-methylpropylamine unit is achievable using this method and chromatographic separation of natural, diatom frustule bound LCPAs extracted from sediment core samples is greatly improved. Using electrospray ionization mass spectrometry (ESI-MS), we detected singly [M+H](+) and multiply [M+nH](n+) charged protonated ions. The abundance of multiply charged LCPA species increased linearly as a function of LCPA chain length (N) and multiprotonated ions [M+nH](n+) were more abundant for longer chain polyamines. The abundance of multiply charged LCPAs along with the concomitant disappearance of the singly charged protonated molecular ion significantly increases the complexity of the MS spectra, justifying the need for good chromatographic separation of complex LCPA mixtures. This analytical procedure will likely constitute a powerful tool for the characterization, quantification, as well as the purification of individual LCPAs in natural and synthetic samples for studies of silica precipitation as well as nitrogen and carbon isotopic analysis used in paleoceanographic studies.

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Synthesis of novel deuterium labelled derivatives of N-alkylated polyamines

Cited by 13 publications

References 52 publications

Metabolism of N-alkylated spermine analogues by polyamine and spermine oxidases

Metabolism of N-alkylated spermine analogues by polyamine and spermine oxidases

Enantioselective synthesis of cyclic and linear diamines by imine cycloadditions

A new liquid chromatography/electrospray ionization mass spectrometry method for the analysis of underivatized aliphatic long‐chain polyamines: application to diatom‐rich sediments

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