103943-63-1

Usage

Uses

Used in Pharmaceutical Industry:
D-Tryptophan, N-[(1,1-dimethylethoxy)carbonyl]-1-methylis used as a building block for the synthesis of peptides and proteins. Its protective group enables specific reactions to take place, facilitating the development of new drugs and therapeutic agents.
Used in Research and Development:
In the field of research and development, D-Tryptophan, N-[(1,1-dimethylethoxy)carbonyl]-1-methylserves as a valuable tool for the exploration and creation of novel pharmaceutical compounds. Its unique properties allow for targeted reactions, contributing to the advancement of drug discovery.
Used in Neuroscience:
D-Tryptophan, N-[(1,1-dimethylethoxy)carbonyl]-1-methylhas potential applications in neuroscience, where it may be utilized in the study and synthesis of neurotransmitters and molecules involved in the regulation of mood and appetite. Its role in this field highlights its importance in understanding and potentially treating neurological disorders.
Used as a Precursor in Synthesis:
Furthermore, D-Tryptophan, N-[(1,1-dimethylethoxy)carbonyl]-1-methylacts as a precursor in the synthesis of certain neurotransmitters and molecules, which are crucial for the proper functioning of the nervous system. Its involvement in this process underscores its significance in the development of treatments for various neurological conditions.

Upstream product

• 862403-33-6 benzyl N^α-(tert-butoxycarbonyl)-1-methyl-D-tryptophanate 
• 5241-64-5 Boc-D-Trp-OH 
• 74-88-4 methyl iodide 
• 24424-99-5 di-tert-butyl dicarbonate 
• 110117-83-4 D-(+)-N_a-methyltryptophan 
• 21339-55-9 1-methyl-L-tryptophan 

Downstream Products

• 862403-35-8 (R)-2-t-butoxycarbonylamino-3-(1-methyl-1H-indol-3-yl)-N-benzyloxypropionamide 
• 1416469-50-5 (4aS,8aR)-2-{1-[(2R)-2-amino-3-(1-methyl-1H-indol-3-yl)propanoyl]piperidin-4-yl}-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydrophthalazin-1(2H)-one 
• 1416467-94-1 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-N-[(2R)-1-{4-[(4aS,8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,6,7,8,8a-hexahydrophthalazin-2(1H)-yl]piperidin-1-yl}-3-(1-methyl-1H-indol-3-yl)-1-oxopropan-2-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide 
• 1416470-20-6 tert-butyl [(2R)-1-{4-[(4aS,8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,6,7,8,8a-hexa-hydrophthalazin-2(1H)-yl]piperidin-1-yl}-3-(1-methyl-1H-indol-3-yl)-1-oxopropan-2-yl]carbamate 
• 862403-33-6 benzyl N^α-(tert-butoxycarbonyl)-1-methyl-D-tryptophanate 
• 110117-83-4 D-(+)-N_a-methyltryptophan 

Relevant academic research and scientific papers

Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands

Chemotherapy with platinum complexes is essential for clinical anticancer therapy. However, due to side effects and drug resistance, further drug improvement is urgently needed. Herein, we report on triple-action platinum(IV) prodrugs, which, in addition to tumor targeting via maleimide-mediated albumin binding, release the immunomodulatory ligand 1-methyl-d-tryptophan (1-MDT). Unexpectedly, structure-activity relationship analysis showed that the mode of 1-MDT conjugation distinctly impacts the reducibility and thus activation of the prodrugs. This in turn affected ligand release, pharmacokinetic properties, efficiency of immunomodulation, and the anticancer activity in vitro and in a mouse model in vivo. Moreover, we could demonstrate that the design of albumin-targeted multi-modal prodrugs using platinum(IV) is a promising strategy to enhance the cellular uptake of bioactive ligands with low cell permeability (1-MDT) and to improve their selective delivery into the malignant tissue. This will allow tumor-specific anticancer therapy supported by a favorably tuned immune microenvironment.

Pentapeptides for the treatment of small cell lung cancer: Optimisation by Nind-alkyl modification of the tryptophan side chain

The pentapeptide, tert-Prenyl4th-NH2 (DMePhe-DTrp-Phe-DTrp(N-tert-prenyl)-Leu-NH2), has recently been reported by our group to exhibit properties of substance P (SP) antagonist G against small cell lung cancer (SCLC). In this study, we undertook a systematic structure activity investigation to optimise this lead compound to improve its in vitro anti-tumour activity and biocompatibility. A series of D-tryptophan (D-Trp) derivatives were synthesised, with a range of aliphatic N-alkyl chains (methyl to pentyl) on the indole nitrogen (Nind). These were incorporated into the pentapeptide sequence by substitution of the Nind-tert-prenylated D-Trp 4th residue with the Nind-alkylated D-Trp derivatives. These pentapeptides were significantly more potent than tert-Prenyl4th-NH2, with the Nind-butyl modification generating the most cytotoxic peptides. Compared to tert-Prenyl4th-NH2, a single butyl modification on the 4th D-Trp residue (Butyl4th-NH2) showed a ～3 fold enhancement in cytotoxicity in either the chemo-naive H69 or the DMS79 (originating from a patient treated with chemotherapeutics and radiation therapy) SCLC cell lines. In addition, the di-butylated sequence on the 2nd and 4th D-Trp residues (Butyl2nd,4th-NH2) gave ～4.5 times higher cytotoxicity against the H69 cell line and a ～2 fold increase against the DMS79 cell line, compared to tert-Prenyl4th-NH2. The favoured position for butyl modification was the 4th D-Trp residue, as the Butyl2nd-NH2 peptide gave lower cytotoxicity on both cell lines. Butylated peptide sequences, when exposed to neat mouse plasma for 24 h at 37 °C, were found to resist degradation with >80% remaining intact compared to ～58% for tert-Prenyl4th-NH2. The degradation pathway in plasma occurs via de-amidation of the C-terminus, confirmed by mass spectrometry and RP-HPLC analysis. The butyl modification also conferred resistance to metabolism when tested using S9 liver fraction from mouse. The optimum analogue responsive against the DMS79 cell line was the Butyl4th-NH2 pentapeptide, which revealed a concentration dependent increase in apoptosis: the level of late apoptotic cells rose from ～36% at 2 μM to ～96% at 6 μM, as determined by flow cytometry, compared to the unmodified peptide that showed no such effect. Concluding, the butyl substitutions offered the best perspective for high cytotoxicity, induction of apoptosis and metabolic compatibility thereby comprising an improved broad spectrum SP antagonist candidate for treatment of SCLC.

A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy

Expression of indoleamine-2,3-dioxygenase (IDO), an immunosuppressive enzyme in human tumors, leads to immune evasion and tumor tolerance. IDO is therefore a tumor immunotherapeutic target, and several IDO inhibitors are currently undergoing clinical trials. IDO inhibitors can enhance the efficacy of common cancer chemotherapeutics. Here we investigate Pt(IV)-(D)-1-methyltryptophan conjugates 1 and 2 for combined immunomodulation and DNA cross-link-triggered apoptosis for cancer "immuno-chemotherapy". Compound 2 effectively kills hormone-dependent, cisplatin-resistant human ovarian cancer cells, inhibiting IDO by transcriptional deregulation of the autocrine-signaling loop IDO-AHR-IL6, which blocks kynurenine production and promotes T-cell proliferation. Additionally, 1 and 2 display low toxicity in mice and are stable in blood. To our knowledge, this construct is the first Pt drug candidate with immune checkpoint blockade properties.

Preparation method of temperature-controlled double-drug preparation and application thereof in tumor postoperative treatment

The invention discloses a preparation method of a temperature-controlled double-drug preparation and application of the temperature-controlled double-drug preparation in tumor postoperative treatment. The preparation method comprises the following steps: preparing 1-methyl tryptophan protected by Boc, then grafting the 1-methyl tryptophan to gelatin, then removing Boc protection in an acidic solution, re-dispersing the obtained solid product in a gelatin aqueous solution to prepare a gelatin solution of modified 1-methyl tryptophan; dispersing a non-steroidal anti-inflammatory drug into the gelatin aqueous solution to prepare a gelatin solution containing the non-steroidal anti-inflammatory drug; and blending the obtained gelatin solutions respectively containing the two drugs to obtain a gelatin mixed solution loaded with the 1-methyl tryptophan and the non-steroidal anti-inflammatory drug at the same time, adding a cross-linking agent to prepare a double-drug preparation precursor solution, and finally placing at 37 DEG C to incubate for different time to obtain different types of drug dosage forms. The double-drug preparation has good bio-compatibility and temperature controllability, is used for adjuvant therapy after tumor resection, and effectively inhibits tumor recurrence and metastasis.

Preparation method and application of compounds and anticancer drugs

The invention provides compounds, which are twin drugs formed by a platinum drug and a small molecule drug covalently connected to the axial position of the platinum drug and having an immune negative modulation relieving function, and have structures as shown in a formula I: wherein the structure of the platinum drug is in a dotted frame; R1 and R2 are the same or different small molecule drugs with the function of relieving immune negative regulation; or one of R1 and R2 is a small molecule medicine with an immune negative regulation relieving function, and the other one is hydroxyl. According to the invention, the small molecule drug with the function of relieving the negative immune regulation is covalently linked to the axial position of the platinum drug to form the twin drug, so that the tumor killing effect of the platinum drug and the function of relieving the negative immune regulation of the small molecule drug are simultaneously exerted at the tumor site; the twin drugs are combined with immunotherapy for use, so that the response of immunotherapy can be effectively improved, and the treatment effect on tumors is remarkably improved. The platinum anticancer twin drug are simple in preparation method, low in cost and suitable for industrial production, and has clinical transformation potential.

Discovery of indoximod prodrugs and characterization of clinical candidate NLG802

A series of different prodrugs of indoximod, including estesrs and peptide amides were synthesized with the aim of improving its oral bioavailability in humans. The pharmacokinetics of prodrugs that were stable in buffers, plasma and simulated gastric and intestinal fluids was first assessed in rats after oral dosing in solution or in capsule formulation. Two prodrugs that produced the highest exposure to indoximod in rats were further tested in Cynomolgus monkeys, a species in which indoximod has oral bioavailability of 6–10percent and an equivalent dose-dependent exposure profile as humans. NLG802 was selected as the clinical development candidate after increasing oral bioavailability (>5-fold), Cmax (6.1–3.6 fold) and AUC (2.9–5.2 fold) in monkeys, compared to equivalent molar oral doses of indoximod. NLG802 is extensively absorbed and rapidly metabolized to indoximod in all species tested and shows a safe toxicological profile at the anticipated therapeutic doses. NLG802 markedly enhanced the anti-tumor responses of tumor-specific pmel-1 T cells in a melanoma tumor model. In conclusion, NLG802 is a prodrug of indoximod expected to increase clinical drug exposure to indoximod above the current achievable levels, thus increasing the possibility of therapeutic effects in a larger fraction of the target patient population.

Dual-functional conjugates improving cancer immunochemotherapy by inhibiting tubulin polymerization and indoleamine-2,3-dioxygenase

A series of novel conjugates comprising tublin and IDO inhibitors were designed, synthesized and evaluated for their antiproliferative activity. Among them, HI5, composed of combretastatin A-4 (CA-4) and (D)-1-methyltryptophan (D-MT) by a linker, exhibited the most potent antitumor activity, in particular with higher IC50 value (0.07 μM) than CA-4 (0.21 μM) against HeLa cancer cell line. Mechanism studies indicated that HI5 can inhibit tubulin polymerization and cell migration, cause G2/M phase arrest, concurrent induce apoptosis via the mitochondrial dependent apoptosis pathway and cause reactive oxidative stress generation in HeLa cells. Furthermore, HI5 can inhibit IDO expression and decrease kynurenine production, leading to stimulating T cells activation and proliferation to enhance antitumor immunity in vitro. Interestingly, HI5 can effectively limit the tumor growth in the HeLa xenograft mice models without causing significant loss of body weight. Consequently, such a conjugation can be a potent and safe immunochemotherapeutic method for improving cancer therapy.

NANO-ENABLED IMMUNOTHERAPY IN CANCER

In certain embodiments a platform technology for the facilitating immune therapy in the treatment of cancer is provided. In certain embodiments nanocarriers are provided that facilitate delivery of an IDO inhibitor in conjunction with an inducer of cell death (ICD-inducer). In certain embodiments the IDO inhibitor is conjugated to a component of a lipid bilayer forming a nanovesicle. In still another embodiment, methods and compositions are provided where an ICD-inducing agent (e.g., doxorubicin, oxaliplatin, mitoxantrone etc.) and an IDO pathway inhibitor (e.g., an IDO inhibitor-prodrug) are integrated into a nanocarrier (e.g. a lipid-bilayer (LB)-coated nanoparticle), that allows systemic delivery to orthotopic pancreatic cancer site.

1-methyltryptophan immune prodrug micelle carrying chemotherapeutic drugs, preparation method and application thereof

The present invention discloses a 1-methyltryptophan immune prodrug micelle carrying chemotherapeutic drugs, a preparation method and an application thereof, and relate to the technical fields of highpolymer materials and new dosage forms of pharmaceutical preparations. The immune prodrug micelle is an indoleamine 2,3 dioxygenase (IDO) inhibitor 1-methyl tryptophan with a tumor immunoregulatory function, chemical bonding with the 1-methyl tryptophan is used to prepare an immunomodulation prodrug carrier, and physical encapsulation of the chemotherapeutic drugs is also conducted to prepare the1-methyltryptophan prodrug micelle carrying the chemotherapeutic drugs with chemotherapy-immunity combined anti-tumor efficacy. Based on a chemotherapy combined with immune anti-tumor strategy, intracellularly released 1-methyl tryptophan inhibits high expression of immunosuppressive protein IDO through inhibition of tumor microenvironment, inhibits IDO-mediated tumor immune escape, at the same time combines anti-tumor functions of the chemotherapeutic drugs, and achieves chemotherapy combined immune synergy against tumors. The 1-methyltryptophan immune prodrug micelle also provides a new multifunctional nanocarrier and a preparation application strategy based on the immunochemotherapy combined with tumor prevention.

SALTS AND PRODRUGS OF 1-METHYL-D-TRYPTOPHAN

Presently provided are indoximod prodrug and salt compounds and pharmaceutical compositions comprising salts and prodrugs of indoximod, that produce enhanced plasma concentration and exposure to indoximod compared to direct administration of indoximod, in