Name: Boc-Val-Cit-OH
Brand: BOC Sciences
Rating: 5 (1 reviews)

Synonyms

(2S)-5-(carbamoylamino)-2-[[(2S)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoyl]amino]pentanoic acid

IUPAC Name

Canonical SMILES

CC(C)C(C(=O)NC(CCCNC(=O)N)C(=O)O)NC(=O)OC(C)(C)C

InChI

InChI=1S/C16H30N4O6/c1-9(2)11(20-15(25)26-16(3,4)5)12(21)19-10(13(22)23)7-6-8-18-14(17)24/h9-11H,6-8H2,1-5H3,(H,19,21)(H,20,25)(H,22,23)(H3,17,18,24)/t10-,11-/m0/s1

InChIKey

ZZLNUAVYYRBTOZ-QWRGUYRKSA-N

Density

1.2±0.1 g/cm3

Solubility

10 mm in DMSO

Flash Point

331.7±31.5 °C

Index Of Refraction

1.504

Vapor Pressure

0.0±3.9 mmHg at 25°C

Appearance

Solid

Shelf Life

0-4°C for short term (days to weeks), or -20°C for long term (months).

Shipping

Room temperature

Storage

Store at -20 °C, keep in dry and avoid sunlight.

Boiling Point

624.8±55.0 °C at 760 mmHg

Form

Solid

Biological Activity

Boc-Val-Cit-OH is a cleavable ADC linker used in the synthesis of antibody-drug conjugates (ADCs)[1] . In Vitro: ADCs are comprised of an antibody to which is attached an ADC cytotoxin through an ADC linker

Boc-Val-Cit-OH, also known as N-tert-butoxycarbonyl-L-valyl-L-citrulline, is a chemical compound prominently used in biochemical research and drug development. This compound features a tert-butoxycarbonyl (Boc) protective group, which is critical for peptide synthesis as it prevents side reactions during the construction of peptide chains. Boc-Val-Cit-OH is particularly valued for its role in the synthesis of protease substrates and inhibitors, primarily within the pharmaceutical sector. Due to its stability and ease of removal, the Boc group is frequently employed to protect amino acids during peptide coupling reactions. This preservation allows researchers to manipulate and study the sequences of amino acids accurately without interference, making Boc-Val-Cit-OH a staple reagent for chemists and biochemists pursuing advanced drug formulations and therapeutic discoveries.

One of the key applications of Boc-Val-Cit-OH lies in the design of prodrugs, especially within cancer therapy. Prodrugs are inactive compounds that can be converted into active drugs upon exposure to specific conditions in the body. Boc-Val-Cit-OH is often integrated into drug-linker systems used in antibody-drug conjugates (ADCs). In this application, the compound serves as a cleavable linker that is stable in the bloodstream but undergoes cleavage due to enzymatic action in the tumor microenvironment. This selective activation is crucial, as it allows the cytotoxic drugs to target and destroy cancer cells while minimizing damage to healthy tissues, significantly enhancing the therapeutic index of the treatment. Consequently, the use of Boc-Val-Cit-OH in ADCs exemplifies a strategic advancement in precision oncology, offering potential breakthroughs in treating various cancers with increased efficacy and reduced side effects.

Furthermore, Boc-Val-Cit-OH is utilized in the development of controlled release systems for drugs. The ability to manipulate its chemical structure allows developers to design systems wherein the drug is released in specific environments or over a timed period. This technology is particularly invaluable in chronic disease management, where maintaining consistent drug levels in the system can improve treatment efficacy and patient compliance. By varying the linkers and modifying the Boc group in the compound, researchers can fine-tune the degradation process, optimizing it for a broad spectrum of therapeutic requirements. This adaptability not only enhances the precision of drug delivery systems but also significantly expands the potential applications of Boc-Val-Cit-OH beyond oncology, into other areas such as immunology, infectious diseases, and metabolic disorders.

1. Inhibition of porcine pepsin by two substrate analogues containing statine. The effect of histidine at the P2 subsite on the inhibition of aspartic proteinases

J Maibaum, D H Rich J Med Chem. 1988 Mar;31(3):625-9. doi: 10.1021/jm00398a022.

Two new inhibitors, 4 and 5, of the aspartic proteinase porcine pepsin were synthesized. These compounds, which span the P4-P'3 binding subsites of the enzyme, were derived by replacing the Nph-Phe dipeptidyl unit of a good pepsin substrate, H2N-Phe-Gly-His-Nph-Phe-Ala-Phe-OMe (3), with statine [(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, Sta]. Hexapeptide 5, H2N-Phe-Gly-Val-(S,S)-Sta-Ala-Phe-OMe, is an extremely potent inhibitor of pepsin with a Ki value less than 1 nM. This result is consistent with the proposal that statine functions as a bioisosteric replacement for a substrate dipeptidyl unit. Compound 4, which contains His at P2, is 2 orders of magnitude less active than the valine analogue 5 (Ki = 150 nM). The factor for the decrease in binding to pepsin effected by replacement of Val by His at P2 parallels the ratio of protonated vs unprotonated imidazole group in peptide 4 at pH 4, according to the Henderson-Hasselbach equation. This result suggests that a positively charged side chain at P2 is undesirable for maximum pepsin inhibition. Kinetic constants for several known inhibitors of pepsin and renin are presented that demonstrate that the effect of His incorporation at P2 on pepsin inhibition depends upon the peptide sequence and that the effect is considerably different for renin inhibitors. We further suggest that the high selectivity of potent renin inhibitors known to be only weak pepsin and cathepsin D inhibitors is due in part to the extent of histidine protonation at P2 arising from pH differences in the inhibition kinetics assay of renin (neutral conditions) compared to other aspartic proteinases (acid pH 2-4).

2. Inhibition of aspartic proteases by pepstatin and 3-methylstatine derivatives of pepstatin. Evidence for collected-substrate enzyme inhibition

D H Rich, M S Bernatowicz, N S Agarwal, M Kawai, F G Salituro, P G Schmidt Biochemistry. 1985 Jun 18;24(13):3165-73. doi: 10.1021/bi00334a014.

The synthesis of 10 analogues of pepstatin modified so that statine is replaced by 4-amino-3-hydroxy-3,6-dimethylheptanoic acid (Me3Sta) or 4-amino-3-hydroxy-3-methyl-5-phenylpentanoic acid (Me3AHPPA) residues is reported. Both the 3S,4S and 3R,4S diastereomers of each analogue were tested as inhibitors of the aspartic proteases, porcine pepsin, cathepsin D, and penicillopepsin. In all cases the 3R,4S diastereomer (rather than the 3S,4S diastereomer) of the Me3Sta and Me3AHPPA derivatives was found to be the more potent inhibitor of the aspartic protease (Ki = 1.5-10 nM for the best inhibitors), in contrast to the results obtained with statine (Sta) or AHPPA derivatives, where the 3S,4S diastereomer is the more potent inhibitor for each diastereomeric pair of analogues. The Me3Sta- and Me3AHPPA-containing analogues are only about 10-fold less potent than the corresponding statine and AHPPA analogues and 100-1000-fold more potent than the corresponding inhibitors lacking the C-3 hydroxyl group. Difference NMR spectroscopy indicates that the (3R,4S)-Me3Sta derivative induces conformational changes in porcine pepsin comparable to those induced by the binding of pepstatin and that the (3S,4S)-Me3Sta derivatives do not induce the difference NMR spectrum. These results require that the C-3 methylated analogues of statine-containing peptides must inhibit enzymes by a different mechanism than the corresponding statine peptides. It is proposed that pepstatin and (3S)-statine-containing peptides inhibit aspartic proteases by a collected-substrate inhibition mechanism. The enzyme-inhibitor complex is stabilized, relative to pepstatin analogues lacking the C-3 hydroxyl groups, by the favorable entropy derived when enzyme-bound water is returned to bulk solvent.(ABSTRACT TRUNCATED AT 250 WORDS)

3. Inhibition of aspartic proteinases by peptides containing lysine and ornithine side-chain analogues of statine

F G Salituro, N Agarwal, T Hofmann, D H Rich J Med Chem. 1987 Feb;30(2):286-95. doi: 10.1021/jm00385a010.

The synthesis of two new analogues of statine are reported corresponding to analogues with the lysine side chain and the ornithine side chain. These analogues were designed on the basis of substrate specificity and molecular modeling of three-dimensional structures of the penicillopepsin: Iva-Val-Sta-OEt crystal structure. 4,8-Diamino-3-hydroxyoctanoic acid [LySta] and 4,7-diamino-3-hydroxyheptanoic acid [OrnSta] were synthesized respectively from Boc-Lys(Z)-al and Boc-Orn(Bzl,Z)-al by addition of lithio ethyl acetate to the aldehyde group. The [LySta] derivative was converted to the trichloroethoxycarbonyl derivative and separated into the corresponding 3S,4S and 3R,4R diastereomers. The [OrnSta] derivative was used as a mixture of 3-position diastereomers. These new amino acids were used to prepare the following inhibitors: Iva-Val-Val-[LySta]-OEt and Iva-Val-Val-[OrnSta]-OEt as well as the corresponding synthetic intermediates. Inhibition constants (Ki values) were measured for inhibition of porcine pepsin and penicillopepsin. Both compounds were potent inhibitors of penicillopepsin with Ki values 10-100 times smaller (2.1 and 1.1 nM, respectively) than the Ki of Iva-Val-Val-Sta-OEt (47 nM). In contrast both inhibitors are exceptionally weak inhibitors of porcine pepsin with Ki values greater than 1 microM. These results are correlated with the ability of the basic group in the new inhibitors to bind to aspartic acid-77 in penicillopepsin.