N-Methyl-N-(t-Boc)-PEG4-acid

Name: N-Methyl-N-(t-Boc)-PEG4-acid
Brand: BOC Sciences
Rating: 5 (1 reviews)

CAS No.: 1260431-01-3

Cat No.: BP-500407 4.5

N-Methyl-N-(t-Boc)-PEG4-acid is a protected polyethylene glycol (PEG) linker building block featuring a four-unit PEG chain terminated by a carboxylic acid, with the PEG backbone capped by an N-methyl, N-(tert-butoxycarbonyl) (Boc) substituted amine. The Boc group provides temporary protection during synthesis, while the terminal acid enables straightforward conjugation to amine-bearing ligands or coupling handles used in PROTAC assembly. In targeted protein degradation design, PEG linkers are widely employed to tune linker length, solubility, and conformational flexibility, helping the resulting PROTAC maintain productive geometry for simultaneous engagement of the target-binding ligand and the E3 ligase recruiter. This compound’s combination of a defined PEG spacer and orthogonally protected functional groups makes it valuable for constructing degraders with improved aqueous handling and systematic optimization of linker-mediated cooperativity, which can be critical for achieving efficient ternary complex formation and degradation potency.

Structure of 1260431-01-3

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PROTAC Linker

Molecular Formula

C₁₇H₃₃NO₈

Molecular Weight

379.45

* For research and manufacturing use only. Not for human or clinical use.

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Please store the product under the recommended conditions in the Certificate of Analysis.

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IUPACName

3-[2-[2-[2-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid

InChI Key

SZYFMMNWNDIBGM-UHFFFAOYSA-N

InChI

InChI=1S/C17H33NO8/c1-17(2,3)26-16(21)18(4)6-8-23-10-12-25-14-13-24-11-9-22-7-5-15(19)20/h5-14H2,1-4H3,(H,19,20)

SMILES

CC(C)(C)OC(=O)N(C)CCOCCOCCOCCOCCC(=O)O

1. Probes for narcotic receptor mediated phenomena. 17. Synthesis and evaluation of a series of trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacet amide (U50,488) related isothiocyanate derivatives as opioid receptor affinity ligands

B R de Costa, R B Rothman, V Bykov, L Band, A Pert, A E Jacobson, K C Rice J Med Chem. 1990 Apr;33(4):1171-6.doi: 10.1021/jm00166a014.

A series of U50,488 related isothiocyanates was synthesized from enantiomerically pure (S,S)-(+)-trans-2-pyrrolidinyl-N-methylcyclohexylamine [(+)-7] and (R,R)-(-)-trans-2-pyrrolidinyl-N-methylcyclohexylamine [(-)-7]. DCC coupling of (+)- and (-)-7 with nitrophenylacetic acids followed by catalytic hydrogenation and treatment with thiophosgene afforded a series of six isomeric aryl isothiocyanate analogues of U50,488. Similarly, DCC coupling of (+)- and (-)-7 with (+)- and (-)-N-t-Boc-protected phenylglycines afforded four isomeric alkyl isothiocyanates. Evaluation of the isothiocyanates for their capacity to produce wash-resistant inhibition of mu, delta, and kappa sites in vitro was performed using rat and guinea pig brain membranes. None of the compounds was able to irreversibly inhibit binding of [3H]bremazocine to guinea pig and rat brain membranes (depleted of functional mu and delta receptors by pretreatment with acylating agents BIT and FIT). However, (1S,2S)-trans-2-isothiocyanato-N-methyl-N-[2- (1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-1] was able to specifically and irreversibly inhibit kappa receptors labeled by [3H]-U69,593: Incubation of rat brain membranes for 60 min at 25 degrees C with 1 microM of (-)-1 resulted in a wash-resistant reduction of the binding to 11.2 +/- 2.5% of the control. Binding analysis revealed the wash-resistant reduction in [3H]-U69,593 binding by (-)-1 to be through an increase in the Kd without effect on the Bmax. (-)-1 failed to effect mu or delta binding in rat or guinea pig brain under the same conditions. The enantiomer of (-)-1, (1R,2R)-trans-2-isothiocyanato-N-methyl-N-[2- (1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(+)-1], failed to affect kappa receptors labeled by [3H]-U69,593 under the same conditions as for (-)-1. (1S,2S)-trans-3-Isothiocyanato-N-methyl-N-[2- (1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-2] inhibited to 49.6 +/- 5.1% of the control, in a wash-resistant manner, kappa receptors labeled by [3H]-U69,593. However, (-)-2 was not as selective as (-)-1 since it also reduced [3H]DADLE (delta) binding to 82.4 +/- 8.0% of the control value. (1S,2S)-trans-4-Isothiocyanato-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzeneacetamide [(-)-3] exhibited selective wash-resistant inhibition of delta receptors labeled by [3H]DADLE resulting in a reduction in binding to 42.9 +/- 4.2% of control.(ABSTRACT TRUNCATED AT 400 WORDS)

2. Alterations in the stereochemistry of the kappa-selective opioid agonist U50,488 result in high-affinity sigma ligands

B R de Costa, W D Bowen, S B Hellewell, C George, R B Rothman, A A Reid, J M Walker, A E Jacobson, K C Rice J Med Chem. 1989 Aug;32(8):1996-2002.doi: 10.1021/jm00128a050.

The synthesis and in vitro sigma receptor activity of the two diastereomers of U50,488 [(+/-)-2], namely, (1R,2S)-(+)- cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacet ami de [(+)-1] and (1S,2R)-(-)-cis-3,4-dichloro- N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-1], are described. (+)-1 and (-)-1 were synthesized from (+/-)-trans-N-methyl-2-aminocyclohexanol [(+/-)-3]. Pyridinium chlorochromate (PCC) oxidation of the N-t-Boc-protected derivative of (+/-)-3 afforded (+/-)-2-[N- [(tert-butyloxy)carbonyl]-N-methylamino]cyclohexanone [(+/-)-5]. The sequence of enamine formation with pyrrolidine, catalytic reduction, N-deprotection, and optical resolution afforded (1R,2S)-(-)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(-)-10] and (1S,2R)-(+)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(+)-10]. The optical purity (greater than 99.5%) of (-)-10 and (+)-10 was determined by HPLC analysis of the diastereomeric ureas formed by reaction with optically pure (R)-alpha-methylbenzyl isocyanate. The absolute configuration of (-)-10 and (+)-10 was determined by single-crystal X-ray diffractometry of the bis-(R)-mandelate salt. Condensation of optically pure (-)-10 and (+)-10 with 3,4-dichlorophenylacetic acid furnished (+)-1 and (-)-1, respectively. Compounds (+)-1, (-)-1, (-)-2, and (+)-2 were compared for their binding affinities at kappa opioid, sigma, D2-dopamine, and phencyclidine (PCP) receptors in competitive binding assays using [3H]bremazocine ([3H]BREM) or [3H]U69,593, [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [[3H]-(+)-3-PPP], or [3H]-1,3-di(o-tolyl)guanidine ([3H]DTG), [3H]-(-)-sulpiride [[3H]-(-)SULP], and [3H]-1- [1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP), respectively. In the systems examined, (-)-2 exhibited the highest affinity for kappa receptors, with a Ki of 44 +/- 8 nM. However, (-)-2 also showed moderate affinity for sigma receptors, with a Ki of 594 +/- 3 nM [[3H]-(+)-3-PPP]. The (1R,2R)-(+)-enantiomer, (+)-2, had low affinity for both kappa and sigma receptors, exhibiting Ki values of 1298 +/- 49 nM at kappa ([3H]BREM) and 1270 +/- 168 nM at sigma [[3H]-(+)-3-PPP]. In contrast, the chiral cis compounds (+)-1 and (-)-1 showed high affinity for sigma receptors and negligible affinity for kappa opioid receptors in the [3H]BREM assay. Compound (-)-1 exhibited a Ki of 81 +/- 13 nM at sigma receptors [[3H]-(+)-3-PPP] and 250 +/- 8 nM ([3H]DTG).(ABSTRACT TRUNCATED AT 400 WORDS)

N-Methyl-N-(t-Boc)-PEG4-acid, is designed to support PROTAC assembly by combining a hydrophilic polyethylene glycol spacer with a protected carboxylic acid handle. The t-Boc group provides orthogonal protection during synthesis, while the acid functionality enables controlled conjugation to targeting ligands. Its flexible, solvated character can help tune linker length and presentation for efficient ternary complex formation. The detailed structural and reactivity considerations are provided below.

Structure: The molecule contains a polyethylene glycol chain providing conformational flexibility and strong hydrogen-bonding/solvation. A carboxylic acid is present for coupling, while the N-methyl, N-substituted amide/urethane-type functionality is compatible with stepwise protection–deprotection strategies. A t-Boc-protecting group supports orthogonal synthetic handling.

Reactivity: PROTAC construction using this linker typically relies on carboxyl activation followed by amide or related bond formation with amine-bearing ligands under standard coupling conditions. The t-Boc group is expected to be stable to mild coupling reagents but can be removed under acid-mediated conditions to reveal the reactive amine for subsequent steps. Common approaches use activating reagents and polar aprotic solvents to promote efficient coupling while minimizing side reactions.

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* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂