- Hypoxia-activatable nano-prodrug for fluorescently tracking drug release in mice
-
Chemotherapy is one of the commonly used methods to treat various types of cancers in clinic by virtue of its high efficiency and universality. However, strong side effects and low concentration of conventional drugs at the tumor site have always been important factors that plague the chemotherapy effects of patients, further precluding their practical applications. Thereof, to solve the above dilemma, by integration of anticancer drug (nitrogen mustard, NM) into an NIR fluorophore (a dicyanoisophorone derivative), an intelligent prodrug NIR-NM was developed via molecular engineering strategy. Prodrug NIR-NM stimulated in hypoxia condition exhibits significantly higher toxicity to cancer cells than normal cells, essentially reducing the collateral damage to healthy cells and tissues of nitrogen mustard. More importantly, the nanoparticle prodrug FA-lip@NIR-NM showed the advantages of the high accumulation of drug at tumor site and long-circulation capacity in vivo, which endowed it the ability to track the release of the active chemotherapeutic drug and further treat solid tumors.[Figure not available: see fulltext.].
- Li, Haidong,Yao, Qichao,Pu, Zhongji,Chung, Jeewon,Ge, Haoying,Shi, Chao,Xu, Ning,Xu, Feng,Sun, Wen,Du, Jianjun,Fan, Jiangli,Wang, Jingyun,Yoon, Juyoung,Peng, Xiaojun
-
-
Read Online
- N nitrogen mustard derivatives, two N - (2 - chloroethyl) - 1, 4 - phenylenediamine - N' - sixteen-acyl and its preparation method
-
The invention discloses a structural formula of a nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-hexadecanoyl-1,4-phenylenediamine, and a preparation method thereof. The preparation method comprises the following steps: preparing N,N-di(2-chloroethyl)-1,4-phenylenediamine; putting the reaction raw materials comprising the N,N-di(2-chloroethyl)-1,4-phenylenediamine, dichloromethane and triethylamine into a reactor, cooling in ice-water bath, stirring, dropwise adding a mixed solution of hexadecanoyl chloride and dichloromethane into the reactor, removing the ice-water bath after addition, conducting reaction at room temperature for 12 to 14 hours, sequentially performing washing, drying and normal-pressure distillation on the reaction liquid after the reaction is conducted completely, and purifying the distilled filter cake to obtain the product. The arylamine nitrogen mustard derivative provided by the invention can effectively reduce the toxic and side effects of nitrogen mustard on the premise of enhancing the treatment index of the nitrogen mustard, and has sterilization and inflammation-diminishing curative effects to reduce the risk of complication caused by the fact that the immunity is reduced after a patient is subjected to chemical therapy.
- -
-
-
- Hydrogen peroxide-responsive nitrogen mustard anti-tumor pro-drug and preparation method thereof
-
The invention discloses a hydrogen peroxide-responsive nitrogen mustard anti-tumor pro-drug and a preparation method thereof, and belongs to the field of pharmaceutical chemistry. The compound contains an alpha-ketoamide structure and a nitrogen mustard structure, can rapidly respond to H2O2, can be used as the nitrogen mustard anti-tumor pro-drug, has good response effect to H2O2, has high cell selectivity and small toxic and side effects, provides an effective, safe and highly selective anti-tumor drug, enriches the types of nitrogen mustard anti-tumor drugs, and has a good market prospect.
- -
-
Paragraph 0112; 0116-0118
(2019/10/17)
-
- Nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-myristoyl-1,4-phenylenediamine and preparation method thereof
-
The invention particularly discloses a structural formula of a nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-myristoyl-1,4-phenylenediamine, and a preparation method thereof. The preparation method comprises the following steps: preparing N,N-di(2-chloroethyl)-1,4-phenylenediamine; putting the N,N-di(2-chloroethyl)-1,4-phenylenediamine, dichloromethane and triethylamine into a reactor, cooling in ice-water bath, stirring, dropwise adding a mixed solution of myristyl chloride and dichloromethane into the reactor, removing the ice-water bath after addition, reacting at room temperature for 10 to 14 hours, washing the reaction liquid after the reaction is conducted completely, drying with anhydrous cupric sulfate, performing normal-pressure distillation, and purifying the distilled filter cake to obtain the product. The nitrogen mustard derivative provided by the invention can effectively reduce the toxic and side effects of nitrogen mustard on the premise of enhancing the treatment index of the nitrogen mustard, and has sterilization and inflammation-diminishing curative effects to reduce the risk of complication caused by the fact that the immunity is reduced after a patient is subjected to chemical therapy.
- -
-
-
- Pyrazolo [1, 5 - a] pyrimidine nitrogen mustard derivative and its preparation method and tumor therapeutic use
-
The invention relates to pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives or medical salts thereof, as well as application of the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives or the medical salts thereof. The pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives and the medical salts thereof have the structure shown as the formula I. Pharmacological experiments show that the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives and the medical salts thereof have inhibiting effects on the proliferation of various tumor cells. Moreover, the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives are small in toxicity, have the advantages of selectivity on tumor cells, and are dual-functional anti-tumor drugs. Meanwhile, the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives are easy to synthesize, and the overall yields are high. All the advantages show that the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives have great potential of being anti-tumor drugs.
- -
-
-
- Aryl nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-propionyl-1,4-phenylenediamine and preparation method thereof
-
The invention particularly discloses a structural formula and preparation method of an aryl nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-propionyl-1,4-phenylenediamine. The method comprises the following steps: preparing N,N-di(2-chloroethyl)-1,4-phenylenediamine; adding the N,N-di(2-chloroethyl)-1,4-phenylenediamine, dichloromethane and triethylamine into a reactor, cooling in an ice water bath, stirring, and dropwisely adding a propionyl chloride-dichloromethane mixed solution into the reactor; after finishing the dropwise addition, removing the ice water bath, and reacting at room temperature for 4-14 hours; and after the reaction finishes, washing the reaction solution, drying with anhydrous cupric sulfate, carrying out atmospheric distillation, and purifying the filter cake. The aryl nitrogen mustard derivative can effectively lower the toxic and side effects of nitrogen mustards on the premise of enhancing the therapeutic index of the nitrogen mustards, and has the curative effects of killing germs and diminishing inflammation, thereby lowering the risk of complications caused by decrease in immunity of the patient after chemotherapy.
- -
-
-
- Nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-benzoyl-1,4-phenylenediamine and preparation method thereof
-
The invention particularly discloses a structural formula of a nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-benzoyl-1,4-phenylenediamine, and a preparation method thereof. The preparation method comprises the following steps: preparing N,N-di(2-chloroethyl)-1,4-phenylenediamine; putting the N,N-di(2-chloroethyl)-1,4-phenylenediamine, dichloromethane and triethylamine into a reactor, cooling in ice-water bath, stirring, dropwise adding a mixed solution of benzoyl chloride and dichloromethane into the reactor, removing the ice-water bath after addition, conducting reaction at room temperature for 8 to 14 hours, sequentially performing washing, drying and normal-pressure distillation on the reaction liquid after the reaction is conducted completely, and purifying the distilled filter cake to obtain the product. The arylamine nitrogen mustard derivative provided by the invention can effectively reduce the toxic and side effects of nitrogen mustard on the premise of enhancing the treatment index of the nitrogen mustard, and has sterilization and inflammation-diminishing curative effects to reduce the risk of complication caused by the fact that the immunity is reduced after a patient is subjected to chemical therapy.
- -
-
-
- Arylamine nitrogen mustard derivative N,N-bis(2-chloroethyl)-N'-acetyl-1,4-phenylenediamine and preparation method thereof
-
The invention specifically discloses a structural formula of an arylamine nitrogen mustard derivative N,N-bis(2-chloroethyl)-N'-acetyl-1,4-phenylenediamine and a preparation method of the derivative. The method comprises the following steps: preparing N,N-bis(2-chloroethyl)-1,4-phenylenediamine; filling a reactor with N,N-bis(2-chloroethyl)-1,4-phenylenediamine, dichloromethane and triethylamine, cooling in an ice-water bath, stirring, dropwise adding a mixed solution of acetyl chloride and dichloromethane into the reactor, removing the ice-water bath after dropwise adding, reacting at the room temperature for 2-14 hours, washing, drying and distilling after the reaction is completed, purifying the distilled filter cake, thereby obtaining the product. The arylamine nitrogen mustard derivative disclosed by the invention can effectively reduce the toxic or side effects of nitrogen mustard on the premise of enhancing the therapeutic index of the nitrogen mustard and has the curative effects of sterilizing and diminishing inflammation so as to reduce the risk of causing complications due to decrease in immunity after chemotherapy of a patient.
- -
-
-
- Rational design, synthesis and preliminary antitumor activity evaluation of a chlorambucil derivative with potent DNA/HDAC dual-targeting inhibitory activity
-
Histone deacetylases (HDACs) play a pivotal role not only in gene expression but also in DNA repair. Herein, we report the successful design, synthesis and evaluation of a chlorambucil derivative named vorambucil with a hydroxamic acid tail as a DNA/HDAC dual-targeting inhibitor. Vorambucil obtained both potent DNA and HDACs inhibitory activities. Molecular docking results supported the initial pharmacophoric hypothesis and rationalized the potent inhibitory activity of vorambucil against HDAC1, HDAC2 and HDAC6. Vorambucil showed potent antiproliferative activity against all the test four cancer cell lines with IC50 values of as low as 3.2–6.2 μM and exhibited 5.0–18.3-fold enhanced antiproliferative activity than chlorambucil. Vorambucil also significantly inhibits colony formation of A375 cancer cells. Further investigation showed that vorambucil remarkably induced apoptosis and arrested the cell cycle of A375 cells at G2/M phase. Vorambucil could be a promising candidate and a useful tool to elucidate the role of those DNA/HDAC dual-targeting inhibitors for cancer therapy.
- Xie, Rui,Li, Yan,Tang, Pingwah,Yuan, Qipeng
-
supporting information
p. 4415 - 4420
(2017/09/12)
-
- Nitrogen mustard compounds containing hydroxamic acid groups as well as preparation method and application of nitrogen mustard compounds
-
The invention discloses nitrogen mustard compounds containing hydroxamic acid groups as well as a preparation method and an application of the nitrogen mustard compounds and relates to the field of medicinal chemistry. The compounds have the capability of inhibiting cancer cell proliferation, achieve the purpose of treating cancer and particularly have excellent cancer cell proliferation inhibition activity for inhibiting human cutaneous melanoma A375, human cervical carcinoma cells HeLa, human liver cancer cells HepG2, human lung cancer cells A549 and human colon cancer cells HCT116. The compounds have the structure shown in a general formula I, wherein X1, X2, X3, X4 and Z are defined in the specification.
- -
-
Paragraph 0051
(2017/07/20)
-
- Design and synthesis of novel quinazoline nitrogen mustard derivatives as potential therapeutic agents for cancer
-
Thirteen novel quinazoline nitrogen mustard derivatives were designed, synthesized and evaluated for their anticancer activities in vitro and in vivo. Cytotoxicity assays were carried out in five cancer cell lines (HepG2, SH-SY5Y, DU145, MCF-7 and A549) and one normal human cell line (GES-1), in which compound 22b showed very low IC50 to HepG2 (the IC50 value is 3.06 μM), which was lower than Sorafenib. Compound 22b could inhibit cell cycle at S and G2/M phase and induce cell apoptosis. In the HepG2 xenograft model, 22b exhibited significant cancer growth inhibition with low host toxicity in vivo.
- Li, Shilei,Wang, Xiao,He, Yong,Zhao, Mingxia,Chen, Yurong,Xu, Jingli,Feng, Man,Chang, Jin,Ning, Hongyu,Qi, Chuanmin
-
p. 293 - 301
(2013/10/01)
-
- HYPOXIA ACTIVATED DRUGS OF NITROGEN MUSTARD ALKYLATORS
-
Hypoxia activated drug compounds having a structure of formula(I) are useful in the treatment of cancer and other hyperproliferative diseases.
- -
-
Page/Page column 50
(2009/12/23)
-
- Synthesis and antiproliferative activity of some new DNA-targeted alkylating pyrroloquinolines
-
Two novel DNA-direct alkylating agents, consisting of aniline mustard linked to an angular 3H-pyrrolo[3,2-f]quinoline nucleus, were synthetized and assayed for their in vitro antiproliferative activity. Simple convergent synthesis, consisting of separate preparation of 9-chloro-3H-pyrrolo[3,2-f] quinoline and p-amino-aniline derivatives, and following their linkage by substitution reactions 8a, b and 10, yielded the corresponding diol derivatives 7b and 9. Biological properties were evaluated with respect to cell growth inhibition, ability to form cross-links with DNA, and capacity to give rise to a molecular complex with the macromolecule for 7b, 8b, 9 and 10.
- Ferlin,Via, L. Dalla,Gia
-
p. 771 - 777
(2007/10/03)
-
- Synthesis and analysis of urea and carbamate prodrugs as candidates for melanocyte-directed enzyme prodrug therapy (MDEPT).
-
The suitability of 4-di(2-chloroethyl)aminoanilino-4-hydroxyphenethylaminomethanone 2 to act as a prodrug for melanocyte-directed enzyme prodrug therapy (MDEPT) is assessed. Thus its synthesis, ability to generate a cytotoxic agent upon exposure to tyrosinase, and stability within different sera are reported. A comparison is made to illustrate that the new urea prodrug 2 is a more suitable candidate for MDEPT than the corresponding carbamate prodrug 1.
- Jordan, Allan M,Khan, Tariq H,Malkin, Hugh,Osborn, Helen M I
-
p. 2625 - 2633
(2007/10/03)
-
- Self-immolative nitrogen mustard prodrugs for suicide gene therapy
-
Four new potential self-immolative prodrugs derived from phenol and aniline nitrogen mustards, four model compounds derived from their corresponding fluoroethyl analogues and two new self-immolative linkers were designed and synthesized for use in the suicide gene therapy termed GDEPT (gene-directed enzyme prodrug therapy). The self-immolative prodrugs were designed to be activated by the enzyme carboxypeptidase G2 (CPG2) releasing an active drug by a 1,6-elimination mechanism via an unstable intermediate. Thus, N-[(4-{[4-(bis{2- chloroethyl}amino)phenoxycarbonyloxy]methyl}phenyl)carbamoyl]-L-glutamic acid (23), N-[(4-{[4(bis{2- chloroethyl}amino)phenoxycarbonyloxy]methyl}phenoxy)carbonyl]-L-glutamic acid (30), N-[(4-{N-(4-(bis[2- chloroethyl]amino}}pheny)carbamoyloxy]methyl}phenoxy)carbonyl]-L-glutmic acid (37), and N-[(4-{[N-(4-{bis[2- chloroethyl]amino}phenyl)carbamoyloxy]methyl}phenyl)carbamoyl]-L-glutamic acid (40) were synthesized. They are bifunctional alkylating agents in which the activating effects of the phenolic hydroxyl or amino functions are masked through an oxycarbonyl or a carbamoyl bond to a benzylic spacer which is itself]inked to a glutamic acid by an oxycarbonyl or a carbamoyl bond. The corresponding fluoroethyl compounds 25, 32, 42, and 44 were also synthesized. The rationale was to obtain model compounds with greatly reduced alkylating abilities that would be much less reactive with nucleophiles compared to the corresponding chloroethyl derivatives. This enabled studies of these model compounds as substrates for CPG2, without incurring the rapid and complicated decomposition pathways of the chloroethyl derivatives. The prodrugs were desired to be activated to their corresponding phenol and aniline nitrogen mustard drugs by CPG2 for use in GDEPT. The synthesis of the analogous novel parent drugs (21b, 51) is also described. A colorectal cell line was engineered to express CPG2 tethered to the outer cell surface. The phenylenediamine compounds were found to behave as prodrugs, yielding IC50 prodrug/IC50 drug ratios between 20- and 33-fold (for 37 and 40) and differentials of 12-14-fold between CPG2-expressing and control LacZ- expressing clones. The drugs released are up to 70-fold more potent than 4- [(2-chloroethyl)(2-mesyloxyethyl)amino]benzoic acid that results from the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid (CMBA) which has been used previously for GDEPT. These data demonstrate the viability of this strategy and indicate that self-immolative prodrugs can be synthesized to release potent mustard drugs selectively by cells expressing CPG2 tethered to the cell surface in GDEPT.
- Niculescu-Duvaz, Dan,Niculescu-Duvaz, Ion,Friedlos, Frank,Martin, Janet,Spooner, Robert,Davies, Lawrence,Marais, Richard,Springer, Caroline J.
-
p. 5297 - 5309
(2007/10/03)
-
- New mustard prodrugs for antibody-directed enzyme prodrug therapy: Alternatives to the amide link
-
Antibody-directed enzyme prodrug therapy (ADEPT) is a two-step approach for the treatment of cancer which seeks to generate a potent cytotoxic agent selectively at a tumor site. In this work described the cytotoxic agent is generated by the action of an enzyme CPG2 on a relatively nontoxic prodrug. The prodrug 1 currently on clinical trial is a benzamide and is cleaved by CPG2 to a benzoic acid mustard drug 1a. We have synthesized a series of new prodrugs 3-8 where the benzamide link has been replaced by, for example, carbamate or ureido. Some of these alternative links have been shown to be good substrates for CPG2 and therefore new candidates for ADEPT. The active drugs 3a and 4a derived from the best of these prodrugs are potent cytotoxic agents (1-2 μM) some 100 times more than 1a. The prodrugs 3 and 4 are some 100-200-fold less cytotoxic, in a proliferating cell assay, than their corresponding active drugs 3a and 4a.
- Dowell, Robert I.,Springer, Caroline J.,Davies, David H.,Hadley, Elizabeth M.,Burke, Philip J.,Boyle, F. Thomas,Melton, Roger G.,Connors, Thomas A.,Blakey, David C.,Mauger, Anthony B.
-
p. 1100 - 1105
(2007/10/03)
-
- On the hydrolytic activation of IMET 3106
-
The azomethine IMET 3106, synthesized by Schulze in 1961, was investigated with respect to the pH dependence of its chemical and enzymatic hydrolysis to produce an active alkylating drug.Hereby it was found that the chemical hydrolysis started at pH values as low as pH 5.In presence of cells of the Ehrlich mouse ascites carcinoma, the hydrolysis at pH 6.01 and 6.25 was only 1.3 times greater than that at pH 7.16; the corresponding rates of hydrolysis were between 0.17 and 0.32percent * min-1.Therefore, it can be assumed that both hydrolytic mechanisms will not sufficiently activate the compound IMET 3106, in tumors acidified by hyperglycemia (cancer multistep therapy) either.
- Ardenne, M. von,Reitnauer, P. G.,Schulze, W.
-
-
- Substituted aminophenyl urea derivatives
-
A substituted aminophenylurea derivative represented by the general formula STR1 wherein X1 and X2 are identical or different and each represents a halogen atom, and R represents a substituted or unsubstituted saturated or unsaturated aliphatic hydrocarbon group, and an acid addition salt thereof, and a process for preparation thereof, the compound of formula (I) being useful as antitumor agent.
- -
-
-