CN115068495B - 核苷单体在制备抗肿瘤的药物中的用途 - Google Patents
核苷单体在制备抗肿瘤的药物中的用途 Download PDFInfo
- Publication number
- CN115068495B CN115068495B CN202210783673.3A CN202210783673A CN115068495B CN 115068495 B CN115068495 B CN 115068495B CN 202210783673 A CN202210783673 A CN 202210783673A CN 115068495 B CN115068495 B CN 115068495B
- Authority
- CN
- China
- Prior art keywords
- lung cancer
- guanosine
- nucleoside
- cells
- kras mutant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000002777 nucleoside Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims description 6
- 150000003833 nucleoside derivatives Chemical class 0.000 title abstract description 14
- 239000000178 monomer Substances 0.000 title abstract description 13
- 239000002246 antineoplastic agent Substances 0.000 title abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 title abstract description 6
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical group C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 claims abstract description 54
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 claims abstract description 27
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229940029575 guanosine Drugs 0.000 claims abstract description 27
- 239000000203 mixture Substances 0.000 claims abstract description 16
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229940104302 cytosine Drugs 0.000 claims abstract description 14
- -1 cytosine nucleoside Chemical class 0.000 claims abstract description 13
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 claims abstract description 7
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 claims abstract description 7
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims description 21
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 16
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 44
- 201000005202 lung cancer Diseases 0.000 abstract description 44
- 208000020816 lung neoplasm Diseases 0.000 abstract description 44
- 230000000694 effects Effects 0.000 abstract description 20
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 230000002147 killing effect Effects 0.000 abstract description 6
- 238000011160 research Methods 0.000 abstract description 5
- 230000002195 synergetic effect Effects 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 32
- 101150105104 Kras gene Proteins 0.000 description 12
- 229940079593 drug Drugs 0.000 description 9
- 102100030708 GTPase KRas Human genes 0.000 description 6
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 6
- 125000003835 nucleoside group Chemical group 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 5
- 206010064571 Gene mutation Diseases 0.000 description 4
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 229930010555 Inosine Natural products 0.000 description 2
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 229960003786 inosine Drugs 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- UYTPUPDQBNUYGX-UHFFFAOYSA-N Guanine Natural products O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 1
- 206010069755 K-ras gene mutation Diseases 0.000 description 1
- 206010027458 Metastases to lung Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- OIRDTQYFTABQOQ-UHFFFAOYSA-N ara-adenosine Natural products Nc1ncnc2n(cnc12)C1OC(CO)C(O)C1O OIRDTQYFTABQOQ-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000005773 cancer-related death Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 239000005549 deoxyribonucleoside Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 208000004124 rheumatic heart disease Diseases 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
- A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了核苷单体在制备抗肿瘤的药物中的用途,属于生物医药材料技术领域。本发明中所述的核苷单体为鸟嘌呤核苷或鸟嘌呤核苷和胞嘧啶核苷组成的组合物。本发明通过研究意外的发现鸟嘌呤核苷(G)对于Kras突变的肺癌细胞具有选择性杀伤效果,有望用于治疗Kras突变型肺癌;并且鸟嘌呤核苷(G)与胞嘧啶核苷(C)混合使用对于肺癌细胞活性抑制可以发挥协同增效作用,提高肺癌治疗效果。本发明为临床肺癌治疗提供了新的治疗思路和方法,具有重要意义。
Description
技术领域
本发明属于生物医药材料技术领域,具体涉及核苷单体在制备抗肿瘤的药物中的用途。
背景技术
肺癌是世界范围内死亡率最高的恶性肿瘤,占所有癌症相关死亡的27%,2021年全球有超过180万人死于肺癌。迄今为止,肺癌一般分为两大类:非小细胞肺癌(NSCLC,80%)和小细胞肺癌(SCLC,20%)。目前,肺癌的总体5年生存率低于18%,其原因在于肺癌是一类异质性很强的恶性肿瘤,不同病因、不同驱动基因的肺癌都必须使用不同的治疗手段。但是,目前针对肺癌的手术切除、放射疗法和药物治疗(靶向与免疫疗法)等都不能完全满足临床需求。因此,对于肺癌药物进行研发,对于提高肺癌患者的总体生存率具有重要意义。
在肺癌中,KRAS是肺癌中一种最常见的突变基因,发生在大约25%的肺腺癌中。KRAS基因突变主要发生在外显子2、3、4上。近年来的研究越来越明确认定KRAS基因突变对NSCLC患者是一个不良的治疗和预后因素。KRAS基因突变会导致对上游EGFR靶点耐药,同时KRAS基因突变会导致肺癌发生脑转移及在肺内转移的风险上升。KRAS突变型非小细胞肺癌的耐药性和高转移性导致患者总体生存率明显低于野生型KRAS患者。并且,由于KRAS突变型非小细胞肺癌的耐药性和高转移性,普通治疗肺癌的药物效果欠佳。而现有技术中,缺乏针对性治疗KRAS突变型非小细胞肺癌的药物。
核苷是一类糖苷的总称,核苷都是由D-核糖或D-Z-脱氧核糖与嘧啶碱或嘌呤碱缩合而成。核苷一般为无色结晶,不溶于普通有机溶剂,易溶于热水,熔点为160~240℃。由D-核糖生成的核苷称核糖核苷,参与RNA组成,由D-α-脱氧核糖生成的核苷称脱氧核糖核苷,参与DNA组成。常见的核苷有:尿嘧啶核苷、腺嘌呤核苷、胞嘧啶核苷、鸟嘌呤核苷、胸腺嘧啶核苷。核苷是核酸的主要组分。有些核苷及其衍生物具有显著的生理功能,如次黄嘌呤核苷(肌苷)可治疗急性和慢性肝炎及风湿性心脏病,并有增加白血球等功效。5-氟尿嘧啶脱氧核苷能抗肿瘤,毒性比5-氟尿嘧啶低,对肝癌、胃癌、直肠癌、卵巢癌、膀胱癌有一定疗效。胞嘧啶阿拉伯糖苷对缓解白血病有显著效果。5′-脱氧-5′-碘尿嘧啶核苷是治疗病毒性角膜炎的特效药。
目前尚未见有研究表明鸟嘌呤核苷(G)与胞嘧啶核苷(C)单体对肺癌细胞活性有抑制作用,更未见鸟嘌呤核苷与胞嘧啶核苷用于治疗KRAS突变型非小细胞肺癌。
发明内容
本发明的目的是提供核苷单体在制备抗肿瘤的药物中的用途。
本发明提供了鸟嘌呤核苷在制备抗肿瘤药物中的用途。
进一步地,所述药物为预防和/或治疗肺癌的药物;
优选地,所述肺癌为非小细胞肺癌;
更优选地,所述肺癌为Kras突变型非小细胞肺癌。
本发明还提供了一种抗肿瘤的组合物,它包括鸟嘌呤核苷。
进一步地,前述的组合物是由鸟嘌呤核苷和胞嘧啶核苷组成。
进一步地,所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为(1~10):(1~10);
优选地,所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为1:1。
本发明还提供了前述的组合物的制备方法,它包括如下步骤:将鸟嘌呤核苷和胞嘧啶核苷混合,即得。
本发明还提供了前述的组合物在制备抗肿瘤药物中的用途。
进一步地,所述药物为预防和/或治疗肺癌的药物;
优选地,所述肺癌为非小细胞肺癌;
更优选地,所述肺癌为Kras突变型非小细胞肺癌。
本发明还提供了鸟嘌呤核苷和胞嘧啶核苷联用在制备抗肿瘤药物中的用途;
优选地,所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为(1~10):(1~10);
更优选地,所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为1:1。
进一步地,所述药物为预防和/或治疗肺癌的药物;
优选地,所述肺癌为非小细胞肺癌;
更优选地,所述肺癌为Kras突变型非小细胞肺癌。
本发明通过研究意外的发现鸟嘌呤核苷(G)对于Kras突变的肺癌细胞具有选择性杀伤效果,有望用于治疗Kras突变型肺癌;并且鸟嘌呤核苷(G)与胞嘧啶核苷(C)混合使用对于肺癌细胞活性抑制可以发挥协同增效作用,提高肺癌治疗效果。本发明为临床肺癌治疗提供了新的治疗思路和方法,具有重要意义。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
本发明使用的核苷单体的结构:
实施例1、核苷单体的抗癌活性研究
1、实验方法
1.1肺癌细胞系培养
在A549细胞(Kras突变型肺癌细胞)、H1299细胞以及H1975细胞中加入含10%FBS和1%的双抗RPMI-1640培养基,并在37℃下,含有5%的CO2细胞培养箱中进行培养。
1.2核苷单体在细胞增殖抑制实验中的预处理
首先分别精确称量2.8mg鸟苷(G)、2.4mg胞苷(C)以及G和C混合物(混合物中,G为2.8mg,C为2.4mg,摩尔比为1:1),并分别加入600μL纯水溶解。然后在85℃下加热5min,待溶液冷却至室温后,在-20℃下冷冻。加药前,将核苷溶液在室温下解冻后,于在95℃下加热5min。等待溶液冷却至室温后,加药(整个操作中尽量避光)。
1.3细胞增殖抑制实验
将A549细胞、H1299细胞以及H1975细胞(4000个/孔)分别接种于96孔板,并加入相同体积的不同药物(G、C、G/C混合物),各药物均用培养基稀释至不同浓度,药物浓度设为0、3.15、6.25、12.5、25、50以及100μM,培养48h。然后弃去上清液,并用PBS洗去残余药物,每孔加入100μL CCK8工作液,并继续孵育2h,通过酶标仪在450nm处检测各孔的吸光度值。通过公式:细胞存活率=[A(药液)-A(空白)]/[A(对照)-A(空白)]来评估药物对细胞的增殖抑制能力。
2、实验结果
C、G以及G/C混合物对A549细胞、H1299细胞以及H1975细胞的抗肺癌细胞结果如表1所示(表1中NA表示在所设置的最高浓度范围内,核苷单体对细胞没有抑制活性)。本发明研究发现:胞苷(C)对三种细胞均不敏感,无抑制细胞增殖的效果;鸟苷(G)对H1299细胞不敏感,无抑制细胞增殖的效果,对H1975细胞增殖活性抑制效果一般(IC50>100μM),但是出乎意料的是G对A549细胞的杀伤力较强,其IC50值为66.1μM,因此G可以选择性抑制A549细胞增殖活性。
此外,本发明研究还发现:G/C混合物抑制A549细胞增殖活性的IC50值为51.27μM,显著优于单独使用G;同时,与单独使用G和C相比,G/C混合物显著提高了对H1975细胞及H1299细胞增殖活性的抑制效果。说明G和C混合使用可以发挥协同增效作用,增强对肺癌细胞的杀伤效果。
表1.核苷单体的抗肺癌细胞活性
上述实验结果意外发现G对于特殊的突变类型肺癌细胞(A549细胞,Kras突变)具有选择性杀伤效果,同时G和C混合使用对于抑制肺癌细胞活性发挥了协同增效作用。因此,核苷单体G或G/C混合物有望用于治疗肺癌。
综上,本发明通过研究意外的发现鸟嘌呤核苷(G)对于Kras突变的肺癌细胞具有选择性杀伤效果,有望用于治疗Kras突变型肺癌;并且鸟嘌呤核苷(G)与胞嘧啶核苷(C)混合使用对于肺癌细胞活性抑制可以发挥协同增效作用,提高肺癌治疗效果。本发明为临床肺癌治疗提供了新的治疗思路和方法,具有重要意义。
Claims (5)
1.鸟嘌呤核苷在制备预防和/或治疗Kras突变型非小细胞肺癌的药物中的用途。
2.一种由鸟嘌呤核苷和胞嘧啶核苷组成的组合物在制备预防和/或治疗Kras突变型非小细胞肺癌的药物中的用途。
3.根据权利要求2所述的用途,其特征在于:所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为1:1。
4.根据权利要求2或3所述的用途,其特征在于:所述组合物的制备方法包括如下步骤:将鸟嘌呤核苷和胞嘧啶核苷混合,即得。
5.鸟嘌呤核苷和胞嘧啶核苷联用在制备预防和/或治疗Kras突变型非小细胞肺癌的药物中的用途;
所述鸟嘌呤核苷和胞嘧啶核苷的摩尔比为1:1。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210783673.3A CN115068495B (zh) | 2022-07-05 | 2022-07-05 | 核苷单体在制备抗肿瘤的药物中的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210783673.3A CN115068495B (zh) | 2022-07-05 | 2022-07-05 | 核苷单体在制备抗肿瘤的药物中的用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115068495A CN115068495A (zh) | 2022-09-20 |
CN115068495B true CN115068495B (zh) | 2023-08-18 |
Family
ID=83258040
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210783673.3A Active CN115068495B (zh) | 2022-07-05 | 2022-07-05 | 核苷单体在制备抗肿瘤的药物中的用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115068495B (zh) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102172359A (zh) * | 2011-03-02 | 2011-09-07 | 张始状 | 腺苷与核苷组合在制备治疗肿瘤药物中的应用 |
CN106074590A (zh) * | 2014-11-24 | 2016-11-09 | 张始状 | 脱氧嘌呤核苷与其它核苷或碱基组合制备的抗肿瘤药物及其制备方法和应用 |
-
2022
- 2022-07-05 CN CN202210783673.3A patent/CN115068495B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102172359A (zh) * | 2011-03-02 | 2011-09-07 | 张始状 | 腺苷与核苷组合在制备治疗肿瘤药物中的应用 |
CN102499937A (zh) * | 2011-03-02 | 2012-06-20 | 张始状 | 脱氧核苷与核苷组合在制备治疗肿瘤药物中的应用 |
CN106074590A (zh) * | 2014-11-24 | 2016-11-09 | 张始状 | 脱氧嘌呤核苷与其它核苷或碱基组合制备的抗肿瘤药物及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
Guanosine and uridine alleviate airway inflammation via inhibition of the MAPK and NF-κB signals in OVA-induced asthmatic mice;Yujiao Luo等;《Pulmonary Pharmacology & Therapeutics》;第69卷;第1-10页 * |
Also Published As
Publication number | Publication date |
---|---|
CN115068495A (zh) | 2022-09-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5968914A (en) | Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides | |
EP0693077B1 (en) | Antiviral compounds | |
EP2423215A1 (en) | Prodrugs based on gemcitabine structure as well as synthetic method and application thereof | |
AU667676B2 (en) | Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides | |
Lin et al. | Synthesis and anticancer and antiviral activities of various 2'-and 3'-methylidene-substituted nucleoside analogs and crystal structure of 2'-deoxy-2'-methylidenecytidine hydrochloride | |
CN115068495B (zh) | 核苷单体在制备抗肿瘤的药物中的用途 | |
ES2587850T3 (es) | Combinación de desoxinucleósido/nucleósido para usar en el tratamiento de tumores | |
CN102516339A (zh) | 嘧啶并嘧啶化合物及其核苷类似衍生物和制备方法及用途 | |
Boothman et al. | Exploitation of elevated pyrimidine deaminating enzymes for selective chemotherapy | |
CN102125579A (zh) | 5位修饰的2’脱氧胞苷衍生物或其磷酸盐在制药中的新应用 | |
CN105287617A (zh) | 次黄嘌呤、次黄苷、黄嘌呤、黄苷或其任意组合在制备治疗肿瘤药物中的应用 | |
CN106539811B (zh) | 环二核苷酸cGAMP在防治抗肿瘤化药诱发的并发症或降低化疗药诱导的毒副作用中的应用 | |
US4882147A (en) | Novel polynucleotide analogs, methods for inhibiting nucleic acid polymerases and methods for inducing synthesis of interferon | |
CN111233955B (zh) | 一类噻唑酮甲酰胞嘧啶衍生物及其药物用途 | |
US5496810A (en) | Pyrimidine deoxyribonucleoside potentiation of combination therapy based on 5-fluorouracil and interferon | |
CN111358938B (zh) | 人干扰素-ε与干扰素-γ组合药及用途 | |
CN109152791A (zh) | 2',2'-二氟-5-氮杂-2'-脱氧胞苷或其前药治疗tp53 野生型肿瘤的方法 | |
LePage | Manipulation of DNA synthesis in normal and neoplastic tissues with drugs | |
GB2207432A (en) | Nucleic acid derivatives | |
WO1995027493A1 (en) | Pyrimidine deoxyribonucleoside potentiation of combination therapy based on 5-fluorouracil and interferon |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |