Carbamate Function Research Articles

Synthesis and characterization of targeted 17β-hydroxysteroid dehydrogenase type 7 inhibitors

Sex steroid hormones such as estrogen estradiol (E2) and androgen dihydrotestosterone (DHT) are involved in the development of hormone-dependent cancers. Blockade of 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7), a member of the short chain dehydrogenase/reductase superfamily, is thought to decrease E2 levels while increasing those of DHT. Therefore, its unique double action makes this enzyme as an interesting drug target for treatment of breast cancer. The chemical synthesis, molecular characterization, and preliminary biological evaluation as 17β-HSD7 inhibitors of novel carbamate derivatives 3 and 4 are described. Like previous 17β-HSD7 inhibitors 1 and 2, compounds 3 and 4 bear a hydrophobic nonyl side chain at the C-17β position of a 4-aza-5α-androstane nucleus, but compound 3 has an oxygen atom replacing the CH2 in the steroid A-ring C-2 position, while compound 4 has a C17-spiranic E-ring containing a carbamate function. They both inhibited the in vitro transformation of estrone (E1) into E2 by 17β-HSD7, but the introduction of a (17 R)-spirocarbamate is preferable to replacing C-2 methylene with an oxygen atom since compound 4 (IC50 = 63 nM) is an inhibitor 14 times more powerful than compound 3 (IC50 = 900 nM). Furthermore, when compared to the reference inhibitor 1 (IC50 = 111 nM), the use of a C17-spiranic E-ring made it possible to introduce differently the hydrophobic nonyl side chain, without reducing the inhibitory activity.

Lycorine and homolycorine derivatives for chemo-sensitizing resistant human ovarian adenocarcinoma cells

BackgroundMultidrug resistance is the major obstacle to cancer chemotherapy. Modulation of P-glycoprotein and drug combination approaches have been considered important strategies to overcome drug resistance. PurposeAiming at generating a small library of Amaryllidaceae-type alkaloids to overcome drug resistance, two major alkaloids, isolated from Pancratium maritimum, lycorine (1), and 2α-10bα-dihydroxy-9-O-demethylhomolycorine (2), were derivatized, giving rise to nineteen derivatives (3 – 21). MethodsThe main chemical transformation of lycorine resulted from the cleavage of ring E of the diacetylated lycorine derivative (3) to obtain compounds that have carbamate and amine functions (5 - 16), while acylation of compound 2 provided derivatives 17 – 21. Compounds 1 - 21 were evaluated for their effects on cytotoxicity, and drug resistance reversal, using resistant human ovarian carcinoma cells (HOC/ADR), overexpressing P-glycoprotein (P-gp/ABCB1), as model. ResultsExcluding lycorine (1) (IC50 values of 1.2- 2.5 µM), the compounds were not cytotoxic or showed moderate/weak cytotoxicity. Chemo-sensitization assays were performed by studying the in vitro interaction between the compounds and the anticancer drug doxorubicin. Most of the compounds have shown synergistic interactions with doxorubicin. Compounds 5, 6, 9 – 14, bearing both carbamate and aromatic amine moieties, were found to have the highest sensitization rate, reducing the dose of doxorubicin 5–35 times, highlighting their potential to reverse drug resistance in combination chemotherapy. Selected compounds (4 – 6, 9 – 14, and 21), able of re-sensitizing resistant cancer cells, were further evaluated as P-gp inhibitors. Compound 11, which has a para‑methoxy-N-methylbenzylamine moiety, was the strongest inhibitor. In the ATPase assay, compounds 9–11 and 13 behaved as verapamil, suggesting competitive inhibition of P-gp. At the same time, none of these compounds affected P-gp expression at the mRNA or protein level. ConclusionsThis study provided evidence of the potential of Amaryllidaceae alkaloids as lead candidates for the development of MDR reversal agents.

Synthesis of the N‐Amykitanosyl Tetramic Acid Moiety of Amycolamicin

AbstractAn improved five‐step synthetic route from l‐fucose to an N‐glycosyl l‐valine methyl ester has been developed. The new route involves glycosidation of l‐fucose with phenol in a β‐selective manner without protection/deprotection steps and one‐pot stereochemical inversion of a secondary alcohol intermediate and is superior to our previous one both in the number of steps and in overall yield. An N‐glycosyl l‐valine benzyl ester, prepared from l‐fucose in an analogous way, has been elaborated into an N‐amykitanosyl tetramic acid derivative, Li's synthetic intermediate for amycolamicin, via a four‐step sequence which features the utilization of Bestmann's ylide to stereoconvergently construct an N‐glycosyl tetramic acid intermediate in a single step, opening of a cyclic carbonate ring with an amine to regioselectively install a carbamate functionality, and visible light‐mediated oxidative debenzylation of an N,N‐dibenzyl carbamate.

Cyclic carbamates in medicine: A clinical perspective.

Carbamate group is mainly used for designing prodrugs to achieve first-pass and systemic stability against enzyme hydrolysis as the carbamate functionality is recognized by esterase enzymes. As compared to the ester functionality, the carbamate group shows a lesser lability towards enzyme hydrolysis, but a higher susceptibility than amides. Cyclic carbamates present a unique motif in the contemporary drug discovery and development owing to the presence of a polar, and sterically small, constrained Hydrogen-bonding acceptor atom. The metabolic stability of 5/6-membered cyclic carbamates are higher as compared to their acyclic counterparts as the former do not undergo metabolic ring opening under physiological conditions. Besides, the metabolic lability of acyclic carbamates is determined by the degree of substitution at the endocyclic/exocyclic "N" atom, which further enables the design and development of various carbamate drugs or prodrugs. As such, the metabolic stability of carbamates follows the order: Cyclic carbamates > Alkyl-OCO-NH2 » Alkyl-OCO-NHAcyl ∼ Alkyl-OCO-NHAryl ≥ Aryl-OCO-N(endocyclic) ∼ Aryl-OCO-N(Alkyl)2 ≥ Alkyl-OCO-N(endocyclic) ≥ Alkyl-OCO-N(Alkyl)2 ∼ Alkyl-OCO-NHAlkyl » Aryl-OCO-NHAlkyl.

Synthesis and some transformations of new acetophenones with carbamate function

Acylation of methyl- N -phenyl-, 2-(morpholin-4-yl)ethylphenyl-, 2-(pyridin-2-yl)ethylphenyl-carbamates with acetic anhydride in polyphosphoric acid at 50-55°C for 3 h proceeds in the para -position to the carbamate grouping to form the corresponding acetophenones. Acylation under similar conditions of methyl 2-(methoxyphenyl)carbamate occurs in the para -position to the methoxy group with the formation of methyl N -(5-acetyl-2-methoxyphenyl)carbamate. The interaction of para - and ortho -acetyl-substituted methyl- N -phenylcarbamate with N -bromosuccinimide, copper(II) acetate in the presence of dimethylformamide at 80°C and with chloro- and hydrobromic acids in the presence of DMSO in ethyl acetate at 30-33°C yielded methyl {4(2)-[(dimethylamino)(oxo)-acetyl]phenyl}- and N -[4(2)-(2-bromo-2-chloroacetyl)phenyl]-carbamates. Condensation of 2-morpholinoethyl [(pyridin-2-yl)ethyl] N -(4-acetylphenyl)carbamates with 4-methoxybenzaldehyde in the presence of a methanolic KOH solution gave the corresponding chalcones.

Ultra‐Fast Continuous‐Flow Photo‐Thiol‐Ene Functionalization of Conformation‐Controlled Cinchona Alkaloids

AbstractIn this work, we describe ultra‐fast continuous flow photo‐thiol‐ene reactions on cinchona alkaloids derivatives through a control of the reactive conformation in solution. Flow thiol‐ene reactions proceed at 32 °C under light irradiation at 365 nm and require only 2.5 minutes of residence time to reach completion. The short path length of the tubular flow photochemical reactor, which maximizes and homogenizes the photon flux, associated to the fine tuning of the reactive conformation of cinchona alkaloids in solution are the main reasons for the high rates observed. The predominant conformation in solution of cinchona alkaloids was adjusted through the substitution of the hydroxyl group at C9 by a phenyl carbamate function.

Synthesis of Four Steroidal Carbamates with Antitumor Activity against Mouse Colon Carcinoma CT26WT Cells: In Vitro and In Silico Evidence

Colorectal cancer (CRC) is one of the most lethal cancers worldwide. If detected on time, surgery can expand life expectations of patients up to five more years. However, if metastasis has grown deliberately, the use of chemotherapy can play a crucial role in CRC control. Moreover, the lack of selectivity of current anticancer drugs, plus mutations that occur in cancerous cells, demands the development of new chemotherapeutic agents. Several steroids have shown their potentiality as anticancer agents, while some other compounds, such as Taxol and its derivatives bearing a carbamate functionality, have reached the market. In this article, the synthesis, characterization, and antiproliferative activity of four steroidal carbamates on mouse colon carcinoma CT26WT cells are described. Carbamate synthesis occurred via direct reaction between diosgenin, its B-ring modified derivative, and testosterone with phenyl isocyanate under a Brønsted acid catalysis. All obtained compounds were characterized by 1H and 13C Nuclear Magnetic Resonance (NMR), High Resolution Mass Spectroscopy (HRMS); their melting points are also reported. Results obtained from antiproliferative activity assays indicated that carbamates compounds have inhibitory effects on the growth of this colon cancer cell line. A molecular docking study carried out on Human Prostaglandin E Receptor (EP4) showed a high affinity between carbamates and protein, thus providing a valuable theoretical explanation of the in vitro results.

Crystal Structures of Lignocellulosic Furfuryl Biobased Polydiacetylenes with Hydrogen-Bond Networks: Influencing the Direction of Solid-State Polymerization through Modification of the Spacer Length.

We present the topochemical polymerization of two lignocellulosic biobased diacetylenes (DAs) that only differ by an alkyl spacer length of 1 methylene (n = 1) or 3 methylene units (n = 3) between the diyne and carbamate functionalities. Their crystalline molecular organizations have the distinctive feature of being suitable for polymerization in two potential directions, either parallel or skewed to the hydrogen-bonded (HB) network. However, single-crystal structures of the final polydiacetylenes (PDAs) demonstrate that the resulting orientation of the conjugated backbones is different for these two derivatives, which lead to HB supramolecular polymer networks (2D nanosheets) for n = 1 and to independent linear PDA chains with intramolecular HBs for n = 3. Thus, spacer length modification can be considered a new strategy to influence the molecular orientation of conjugated polymer chains, which is crucial for developing the next generation of materials with optimal mechanical and optoelectronic properties. Calculations were performed on model oligodiacetylenes to evaluate the cooperativity effect of HBs in the different crystalline supramolecular packing motifs and the energy profile related to the torsion of the conjugated backbone of a PDA chain (i.e., its ability to adopt planar or helical conformations).

Study of the carbamate/aldehyde reaction, a new pathway towards NIPU materials

An innovative alternative to the synthesis of non-isocyanate polyurethanes (NIPUs) thermoset materials was thoroughly investigated. This pathway, involving the reaction between primary carbamate functions and aldehyde functions, was studied using model reactions between ethyl carbamate and different aldehydes that lead to the highlights of the key parameters as well as the first reported proposed mechanism for this reaction. In a second time, polycarbamates synthesized from two different polyols were synthesized via transcarbamoylation before participating in a polycondensation reaction with different monoaldehydes. First a linear NIPU oligomer was synthesized using a dicarbamate derived from ethylene glycol and benzaldehyde. This product was analysed by NMR spectroscopy and MALDI-TOF mass spectrometry. This oligomer exhibited low molar masses attributed to many secondary termination reactions, mainly due to the presence of acetic anhydride used as solvent in the reaction. Cross-linked NIPU materials were then synthesized without solvent, from the reaction between a tricarbamate derived from trimethylol propane and vanillin, a biobased monoaldehyde, for the first time. The process parameters for the synthesis of these materials were optimized to obtain biobased NIPU thermosetting networks with gel fraction (GF) in dimethylsulfoxide (DMSO) up to 82%, with Tg values ranging between 39 °C and 65 °C depending on the GF value. This study brings a much needed highlight on the little-known carbamate/aldehyde reaction and demonstrates its potential for the synthesis of novel biobased NIPU thermosetting coatings using a simple monoaldehyde such as vanillin.

A Cu(II)-MOF Based on a Propargyl Carbamate-Functionalized Isophthalate Ligand as Nitrite Electrochemical Sensor.

This paper investigates the electrochemical properties of a new Cu(II)-based metal-organic framework (MOF). Noted as Cu-YBDC, it is built upon a linker containing the propargyl carbamate functionality and immobilized on a glassy carbon electrode by drop-casting (GC/Cu-YBDC). Afterward, GC/Cu-YBDC was treated with HAuCl4 and the direct electro-deposition of Au nanoparticles was carried at 0.05 V for 600 s (GC/Au/Cu-YBDC). The performance of both electrodes towards nitrite oxidation was tested and it was found that GC/Au/Cu-YBDC exhibited a better electrocatalytic behavior toward the oxidation of nitrite than GC/Cu-YBDC with enhanced catalytic currents and a reduced nitrite overpotential from 1.20 to 0.90 V. Additionally GC/Au/Cu-YBDC showed a low limit of detection (5.0 μM), an ultrafast response time (<2 s), and a wide linear range of up to 8 mM in neutral pH.

PH/enzyme/light triple‐responsive vesicles from lysine‐based amphiphilic diblock copolymers

AbstractWe report the synthesis of pH‐ and enzyme‐responsive amphiphilic diblock copolymers through reversible addition‐fragmentation chain transfer polymerization of a lysine‐derived methacrylate monomer comprising p‐nitrobenzyl carbamate (pNBC) functionality using a poly(ethylene glycol)‐modified macro‐chain transfer agent. Depending on the hydrophobic block length, the diblock copolymers self‐assemble to form spherical micelles, wormlike micelles, and bilayered vesicles in the aqueous solution. The responsive behaviors of the polymeric vesicles to pH, enzyme, and light are investigated in detail. As the pH lowers to pH 5.0, the polymeric vesicles undergo a morphological transition from vesicles to spherical micelles. In the presence of nitroreductase and a cofactor NADH, the decomposition of pNBC releases the ε‐NH2 of the lysine moiety and hence induces the generation of the vesicles with crosslinked membranes at pH 7.4. Moreover, owing to the degradation of pNBC moiety under UV irradiation, the polymeric vesicles also demonstrate a photo‐responsive feature. As the irradiation time prolongs, it is observed a light‐triggered morphological transition from vesicles to wormlike micelles with network‐like structures.

New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators.

In the last years, the connection between the endocannabinoid system (eCS) and neuroprotection has been discovered, and evidence indicates that eCS signaling is involved in the regulation of cognitive processes and in the pathophysiology of Alzheimer’s disease (AD). Accordingly, pharmacotherapy targeting eCS could represent a valuable contribution in fighting a multifaceted disease such as AD, opening a new perspective for the development of active agents with multitarget potential. In this paper, a series of coumarin-based carbamic and amide derivatives were designed and synthesized as multipotent compounds acting on cholinergic system and eCS-related targets. Indeed, they were tested with appropriate enzymatic assays on acetyl and butyryl-cholinesterases and on fatty acid amide hydrolase (FAAH), and also evaluated as cannabinoid receptor (CB1 and CB2) ligands. Moreover, their ability to reduce the self-aggregation of beta amyloid protein (Aβ42) was assessed. Compounds 2 and 3, bearing a carbamate function, emerged as promising inhibitors of hAChE, hBuChE, FAAH and Aβ42 self-aggregation, albeit with moderate potencies, while the amide 6 also appears a promising CB1/CB2 receptors ligand. These data prove for the new compounds an encouraging multitarget profile, deserving further evaluation.

Effects of C-Terminal B-Chain Modifications in a Relaxin 3 Agonist Analogue.

The receptor for the neuropeptide relaxin 3, relaxin family peptide 3 (RXFP3) receptor, is an attractive pharmacological target for the control of eating, addictive, and psychiatric behaviors. Several structure-activity relationship studies on both human relaxin 3 (containing 3 disulfide bonds) and its analogue A2 (two disulfide bonds) suggest that the C-terminal carboxylic acid of the tryptophan residue in the B-chain is important for RXFP3 activity. In this study, we have added amide, alcohol, carbamate, and ester functionalities to the C-terminus of A2 and compared their structures and functions. As expected, the C-terminal amide form of A2 showed lower binding affinity for RXFP3 while ester and alcohol substitutions also demonstrated lower affinity. However, while these analogues showed slightly lower binding affinity, there was no significant difference in activation of RXFP3 compared to A2 bearing a C-terminal carboxylic acid, suggesting the binding pocket is able to accommodate additional atoms.

Conversion of Isocyanide to Amine in The Presence of Water and Hg(II) Ions: Kinetics and Mechanism as Detected by Fluorescence Spectroscopy and Mass Spectrometry.

Aromatic isocyanides including isocyanonaphthalene derivatives have been proven to be very effective fluorescent sensors for the quantification of Hg(II) ions in water. Thus, the reaction of 1,5-isocyanoaminonaphthalene (1,5-ICAN), which is one of the most important members of this family, with water and HgCl2 as the oxidation agents, was studied by fluorescence spectroscopy and mass spectrometry in order to get deeper insight into the kinetics and mechanistic details of this complex reaction. The reactions of 1,5-ICAN with water and HgCl2 were performed in various water/co-solvent mixtures of different compositions. The co-solvents used in this study were both aprotic solvents including tetrahydrofuran, acetonitrile and N,N-dimethylformamide and protic solvents, such as ethanol and 2-propanol. It was found that in aprotic solvents the conversion of the isocyano group to amino moiety takes place, while in protic solvents the corresponding carbamate (urethane) group is formed in addition to the amino moiety. The variation of the resulting fluorescence intensities versus time curves were described using an irreversible, consecutive reaction model, in which the formation of isocyanate and carbamic acid intermediates, as well as diamino and carbamate (in the case of protic solvents) products were assumed. The formation of these intermediates and products was unambiguously confirmed by mass spectrometric measurements. Furthermore, by fitting the model to the experimental fluorescence versus time curves, the corresponding rate coefficients were determined. It was observed that the overall rate of transformation of the isocyano group to amino moiety increased with the water concentration and the polarity of the co-solvent. It was also supported that formation of diamino and carbamate derivatives in protic solvents takes place simultaneously and that the ratio of the amino to the carbamate function increased with the increasing water concentration. In addition, with an extension, the model presented herein proved to be capable of describing the kinetics of the transformation of 1,5-diisocyanonaphthalene (1,5-DIN) into 1,5-diaminonaphthalene (1,5-DAN) in the mixtures of water/aprotic solvents.

Carbamate-Isocyanurate-Bridged Periodic Mesoporous Organosilica for van der Waals CO2 Capture.

We synthesized a new organosiloxane bridge on the basis of an isocyanurate derivative through a simple melt-fusion approach by the reaction of 3-isocyanatopropyltriethoxysilane (IPTES) with 1,3,5-tris(2-hydroxyethyl)-1,3,5-triazinane-2,4,6(1H,3H,5H)-trione (THEIC). The obtained carbamate-isocyanurate-based organosiloxane bridge precursor was used for the preparation of chemo- and thermostable periodic mesoporous organosilica (PMO-THEIC) on condensation with tetrathoxysilane silicon precursor through a soft-template approach. Furthermore, the synthesized PMO-THEIC with unique surface functionality was investigated for CO2 capture. The results show that the PMO-THEIC has higher activity than pure SBA-15 for CO2 capture due to the high affinity of carbamate functionalities embedded within the pore walls toward CO2 molecules. The affinity of organosiloxane bridge for CO2 molecules is mainly facilitated via the van der Waals force with carbamate functional groups rather than the isocyanurate ring, according to the density functional calculations.

Preparation and Characterization of Novel Mixed Periodic Mesoporous Organosilica Nanoparticles.

We report herein the preparation of mixed periodic mesoporous organosilica nanoparticles (E-Pn 75/25 and 90/10 PMO NPs) by sol-gel co-condensation of E-1,2-bis(triethoxysilyl)ethylene ((E)-BTSE or E) with previously synthesized disilylated tert-butyl 3,5-dialkoxybenzoates bearing either sulfide (precursor P1) or carbamate (precursor P2) functionalities in the linker. The syntheses were performed with cetyltrimethylammonium bromide (CTAB) as template in the presence of sodium hydroxide in water at 80 °C. The nanomaterials have been characterized by Transmission Electron Microscopy (TEM), nitrogen-sorption measurements (BET), Dynamic Light Scattering (DLS), zeta-potential, Thermogravimetric Analysis (TGA), FTIR, 13C CP MAS NMR and small angle X-ray diffraction (p-XRD). All the nanomaterials were obtained as mesoporous rodlike-shape nanoparticles. Remarkably, E-Pn 90/10 PMO NPs presented high specific surface areas ranging from 700 to 970 m2g−1, comparable or even higher than pure E PMO nanorods. Moreover, XRD analyses showed an organized porosity for E-P1 90/10 PMO NPs typical for a hexagonal 2D symmetry. The other materials showed a worm-like mesoporosity.

Regioselective Synthesis of a C-4'' Carbamate,C-6'' n-Pr Substituted Cyclitol Analogue of SL0101.

An asymmetric synthesis of two analogues of SL0101 (1) has been achieved. The effort is aimed at the discovery of inhibitors of the p90 ribosomal S6 kinase (RSK) with improved bioavailability. The route relies upon the use of the Taylor catalyst to regioselectively install C-3″ acetyl or carbamate functionality. This study led to the identification of a third-generation analogue of SL0101 with a C-4″ n-Pr-carbamate and a C-3″ acetate with improved RSK inhibitory activity.

Preparation and Single Crystal Structure Determination of the First Biobased Furan-Polydiacetylene Using Topochemical Polymerization

Crystal structure elucidations of bio-based polymers provide invaluable data regarding structure–property relationships. In this work, we achieved synthesis and Single Crystal X-ray Diffraction (SCXRD) structural determination of a new furan-based polydiacetylene (PDA) derivative with carbamate (urethane) functionality. Firstly, diacetylene (DA) monomers were found to self-assemble in the crystalline state in such a way that the polymerization theoretically occurred in two different directions. Indeed, for both directions, geometrical parameters for the reactive alignment of DA are satisfied and closely related with the optimal geometrical parameters for DA topochemical polymerization (d(1) = 4.7–5.2 Å, d(2) ≤ 3.8 Å, θ ≈ 45°). However, within the axis of hydrogen bonds (HB), the self-assembling monomers display distances and angles (d(1) = 4.816 Å, d(2) = 3.822 Å, θ = 51°) that deviate more from the ideal values than those in the perpendicular direction (d(1) = 4.915Å, d(2) = 3.499Å, θ ≈ 45°). As expected from these observations, the thermal topochemical polymerization occurs in the direction perpendicular to the HB and the resulting PDA was characterized by SCXRD.

Conjugation of Small Molecules to RNA Using a Reducible Disulfide Linker Attached at the 2′‐OH Position through a Carbamate Function

A post‐synthesis conjugation method was developed to functionalize oligoribonucleotides with various small molecules of biological interest using a reduction‐sensitive disulfide linker connected to 2′OH via a carbamate function. For this, first we prepared a 2′‐O‐[(N‐(acetylthio)‐ethylcarbamoyl] (2′‐O‐AcSEC) uridine phosphoramidite as the key precursor of the disulfide linker, that was incorporated into 21‐mer RNAs. Next the 2′‐O‐AcSEC group was converted on solid support to the activated 2′‐O‐[N‐(2‐pyridyldisulfanyl)‐ethylcarbamoyl] (2′‐O‐PySSEC) group. Finally, the coupling between 2′‐O‐PySSEC‐modified RNA and diverse small molecules bearing a thiol function was based on a thiol‐disulfide exchange reaction in solution. Several RNA‐small molecule conjugates were obtained with satisfactory conjugation yields. An RNA was successfully double‐conjugated with an anticancer drug (doxorubicin) attesting the efficiency and the robustness of the conjugation method. We have shown that the disulfide‐linked RNA‐small molecule conjugates were cleaved upon 5.6 mm glutathione treatment, featuring the release of the small molecules in cells.

Reduction and pH dual‐responsive block copolymers containing pendent p‐nitrobenzyl carbamate functionalities: Synthesis and self‐assembly behavior

ABSTRACTWe report on the preparation of reduction‐responsive amphiphilic block copolymers containing pendent p‐nitrobenzyl carbamate (pNBC)‐caged primary amine moieties by reversible addition–fragmentation chain transfer (RAFT) radical polymerization using a poly(ethylene glycol)‐based macro‐RAFT agent. The block copolymers self‐assembled to form micelles or vesicles in water, depending on the length of hydrophobic block. Triggered by a chemical reductant, sodium dithionite, the pNBC moieties decomposed through a cascade 1,6‐elimination and decarboxylation reactions to liberate primary amine groups of the linkages, resulting in the disruption of the assemblies. The reduction sensitivity of assemblies was affected by the length of hydrophobic block and the structure of amino acid‐derived linkers. Using hydrophobic dye Nile red (NR) as a model drug, the polymeric assemblies were used as nanocarriers to evaluate the potential for drug delivery. The NR‐loaded nanoparticles demonstrated a reduction‐triggered release profile. Moreover, the liberation of amine groups converted the reduction‐responsive polymer into a pH‐sensitive polymer with which an accelerated release of NR was observed by simultaneous application of reduction and pH triggers. It is expected that these reduction‐responsive block copolymers can offer a new platform for intracellular drug delivery. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1333–1343