- Single Diastereomers of the Clinical Anticancer ProTide Agents NUC-1031 and NUC-3373 Preferentially Target Cancer Stem CellsIn Vitro
-
A 3′-protected route toward the synthesis of the diastereomers of clinically active ProTides, NUC-1031 and NUC-3373, is described. Thein vitrocytotoxic activities of the individual diastereomers were found to be similar to their diastereomeric mixtures. In the KG1a cell line, NUC-1031 and NUC-3373 have preferential cytotoxic effects on leukemic stem cells (LSCs). These effects were not diastereomer-specific and were not observed with the parental nucleoside analogues gemcitabine and FUDR, respectively. In addition, NUC-1031 preferentially targeted LSCs in primary AML samples and cancer stem cells in the prostate cancer cell line, LNCaP. Although the mechanism for this remains incompletely resolved, NUC-1031-treated cells showed increased levels of triphosphate in both LSC and bulk tumor fractions. As ProTides are not dependent on nucleoside transporters, it seems possible that the LSC targeting observed with ProTides may be caused, at least in part, by preferential accumulation of metabolized nucleos(t)ide analogues.
- Slusarczyk, Magdalena,Serpi, Michaela,Ghazaly, Essam,Kariuki, Benson M.,McGuigan, Christopher,Pepper, Chris
-
-
Read Online
- Influence of 4′-Substitution on the Activity of Gemcitabine and Its ProTide against VZV and SARS-CoV-2
-
In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4′-methoxy- and 4′-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these derivatives, 4′-fluorogemcitabine proved to be active against varicella zoster virus (VZV, TK+ strain) with an EC50 of 0.042 μM and produced significant cytotoxicity (CC50 = 0.11 μM). Upon derivatization of this trifluoro nucleoside as its prodrug, decreased anti-VZV activity was observed, but with a concomitantly improved selectivity index (SI = 36). When this prodrug was tested against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its antiviral activity (EC50 = 0.73 μM) was comparable to or slightly lower than its cytotoxic concentration in measurements of cell growth and cell morphology, respectively.
- Zheng, Zihua,Groaz, Elisabetta,Snoeck, Robert,De Jonghe, Steven,Herdewijn, Piet,Andrei, Graciela
-
-
- Phenylalanine amidated nucleotide derivative and preparation method and application thereof
-
The invention provides a phenylalanine amidated nucleotide derivative and a preparation method and application thereof. Halogenated phenylalanine is combined with amino of an amino-containing nucleoside compound while phosphorylation is performed; through a monophosphate synthesis link for promoting absorption and avoiding speed limiting in a form of phosphate and phosphamide prodrug, action of nucleoside deaminase is reduced or avoided to enhance efficacy; halogenated phenylalanine has synergistic effect in inhibiting protein synthesis, thereby playing a role in improving bioavailability andefficacy and reducing drug tolerance in the antitumor and anti-HBV aspects.
- -
-
-
- Nucleoside phosphate/amide derivative and medical application thereof
-
The invention relates to a nucleoside phosphate/amide derivative shown in the formula I and isomers, nontoxic pharmaceutically acceptable salts and solvates thereof. The formula I is shown in the description. In the formula I, Nu represents nucleoside res
- -
-
-
- Phosphoramidate Compound and Preparation Method and Crystal Thereof
-
The present disclosure involves a composition enriched in compound 61501b, wherein the compound 61501b has a purity of not less than 90% or more. The composition has a significant advantage in preparing a high-purity compound Sp-1. In addition, the present disclosure also provides a preparation method of the composition enriched in compound 61501b. The method adopts a crystallization technique to perform separation and purification, has a simple and convenient operation and good reproducibility, and therefore the compound 61501b in the prepared composition has high purity and quality. Further, the present disclosure also involves a novel crystal form of compound 61501b.
- -
-
-
- Preparation Method of Nucleoside Phosphoramidate Prodrugs and Intermediates Thereof
-
Provided in the present disclosure are a novel preparation method of nucleoside phosphoramidate prodrugs and the intermediates thereof. In particular, the method is adopted to perform isomer separation on the reaction product from a first step and then perform a two-step chemical synthesis, so as to prepare a high-purity compound Sp-1. The method has simple and convenient operation and low cost. The prepared resulting single isomer Sp-1 has high purity, and the HPLC purity thereof is 95% or more, and further, 99% or more. The method is suitable for industrial production and can satisfy the need of clinical study. Further, also provided in the present disclosure are a key intermediate phosphorus reagent for preparing the high-purity compound Sp-1 and the preparation method thereof.
- -
-
-
- Composition Rich in Single Isomer NUC-1031 and Preparation Method and use Thereof
-
Provided is a preparation method of a composition enriched in compound Sp-1. The method performs isomer separation on a reaction product from the first step, and then performs a two-step chemical synthesis, so as to prepare a composition comprising high-purity compound Sp-1, wherein the HPLC purity of the single isomer Sp-1 is 90% or more. Provided is a composition enriched in compound Sp-1. The composition has an inhibitory effect on tumor cell proliferation in vitro significantly higher than that of NUC-1031 and compound Rp-1. Also provided are the use of the composition, and a pharmaceutical composition comprising the composition and at least one pharmaceutically acceptable excipient.
- -
-
-
- COMBINATION THERAPY
-
This invention relates to a combination of gemcitabine-[phenyl-benzoxy-L-alaninyl)]- phosphate (chemical name: 2'-Deoxy-2',2'-difluoro-D-cytidine-5'-O-[phenyl (benzoxy-L- alaninyl)] phosphate)(NUC-1031) and a platinum-based anticancer agent selected from
- -
-
Paragraph 00110
(2017/07/14)
-
- DIASTEREOSELECTIVE SYNTHESIS OF PHOSPHATE DERIVATIVES AND OF THE GEMCITABINE PRODRUG NUC-1031
-
The present invention provides a method for the preparation of intermediates useful in the synthesis of gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate. It also provides a method of preparing gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate.
- -
-
-
- Mechanism-Based Solution to the ProTide Synthesis Problem: Selective Access to Sofosbuvir, Acelarin, and INX-08189
-
A general and efficient method for the synthesis of pronucleotide (ProTide) 5'-phosphoramidate monoesters is reported. This method consists of a highly stereoselective 5'-phosphorylation mediated by dimethylaluminum chloride to afford the desired target ProTides in excellent yields without employing 3'-protection strategies. The application of this methodology to the synthesis of a number of pharmaceutically relevant compounds currently marketed or under investigation in clinical research is demonstrated.
- Simmons, Bryon,Liu, Zhuqing,Klapars, Artis,Bellomo, Ana,Silverman, Steven M.
-
supporting information
p. 2218 - 2221
(2017/05/12)
-
- PROCESS FOR THE PREPARATION OF GEMCITABINE-[PHENYL(BENZOXY-L-ALANINYL)] PHOSPHATE
-
The present invention provides a process for the preparation of gemcitabine-[phenyl(benzoxy-L-alaninyl)] phosphate of Formula I in high yield and purity.
- -
-
-
- Application of ProTide technology to gemcitabine: A successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development
-
Gemcitabine is a nucleoside analogue commonly used in cancer therapy but with limited efficacy due to a high susceptibility to cancer cell resistance. The addition of a phosphoramidate motif to the gemcitabine can protect it against many of the key cancer resistance mechanisms. We have synthesized a series of gemcitabine phosphoramidate prodrugs and screened for cytostatic activity in a range of different tumor cell lines. Among the synthesized compounds, one in particular (NUC-1031, 6f) was shown to be potent in vitro. Importantly, compared with gemcitabine, 6f activation was significantly less dependent on deoxycytidine kinase and on nucleoside transporters, and it was resistant to cytidine deaminase-mediated degradation. Moreover, 6f showed a significant reduction in tumor volumes in vivo in pancreatic cancer xenografts. The ProTide 6f is now in clinical development with encouraging efficacy signals in a Phase I/II study, which strongly supports the ProTide approach to generate promising new anticancer agents.
- Slusarczyk, Magdalena,Lopez, Monica Huerta,Balzarini, Jan,Mason, Malcolm,Jiang, Wen G.,Blagden, Sarah,Thompson, Emely,Ghazaly, Essam,McGuigan, Christopher
-
p. 1531 - 1542
(2014/03/21)
-
- CHEMICAL COMPOUNDS
-
Phosphoramidate derivatives of nucleotides and their use in the treatment of cancer are described. The base moieties of, for example, each of deoxyuridine, cytarabine, gemcitabine and citidine may be substituted at the 5-position. The phosphoramidate moiety has attached to the P atom an aryl-O moiety and an α-amino acid moiety. The α-amino acid moiety may correspond to or be derived from either a naturally occurring or a non-naturally occurring amino acid.
- -
-
Page/Page column 70
(2010/02/10)
-