WO2025146241 - DISCOVERY OF A HIGHLY SELECTIVE AND POTENT PRO-APOPTOTIC ACYCLIC PHOSPHORAMIDATE NUCLEOTIDES FOR HEPATOCELLULAR CARCINOMA
National phase entry is expected:
Publication Number
WO/2025/146241
Publication Date
10.07.2025
International Application No.
PCT/EG2024/000018
International Filing Date
05.09.2024
Title **
[English]
DISCOVERY OF A HIGHLY SELECTIVE AND POTENT PRO-APOPTOTIC ACYCLIC PHOSPHORAMIDATE NUCLEOTIDES FOR HEPATOCELLULAR CARCINOMA
[French]
DÉCOUVERTE DE NUCLÉOTIDES DE PHOSPHORAMIDATE ACYCLIQUE PRO-APOPTOTIQUE HAUTEMENT SÉLECTIF ET PUISSANT POUR LE CARCINOME HÉPATOCELLULAIRE
Applicants **
HAMMAD, Sherif Fouad Aly Mohammed
Inventors
HAMMAD, Sherif Fouad Aly Mohammed
Priority Data
2024010024
03.01.2024
EG
Application details
| Total Number of Claims/PCT | * |
| Number of Independent Claims | * |
| Number of Priorities | * |
| Number of Multi-Dependent Claims | * |
| Number of Drawings | * |
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| Number of Pages with Drawings | * |
| Pages of Specification | * |
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| Number of Office Actions | * |
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International Searching Authority |
EGPO
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| Recordal of a Change of the Applicant's Name/Address |
Change of Applicant's Name and Address
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| Type of Assignment |
The Standard Agent's Assignment
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| Applicant's Legal Status |
Natural Person
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| * | |
| * | |
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| Entry into National Phase under |
Chapter I
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| Patent Delivery |
Send the Letters Patent by Courier
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| Translation |
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* The data is based on automatic recognition. Please verify and amend if necessary.
** IP-Coster compiles data from publicly available sources. If this data includes your personal information, you can contact us to request its removal.
Quotation for National Phase entry
| Country | Stages | Total | |
|---|---|---|---|
| China | Filing, Examination, Granting | 1958 | |
| EPO | Filing, Examination, Granting | 8677 | |
| Japan | Filing, Examination, Granting | 1907 | |
| South Korea | Filing, Examination, Granting | 1603 | |
| USA | Filing, Examination, Granting | 7140 |
Total:
21,285
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Abstract[English]
A series of non-cyclic phosphoramidate nucleotide analogs were synthesized through two chemical reactions. The first is a multi-component reaction (MCR) that produces acridinedione derivatives (7a-e). The second step provides non-cyclic phosphoramidate derivatives (9a-e). The non-cyclic nucleosides (7a-e) and their corresponding non-cyclic phosphoramidate derivatives (9a-e) were evaluated for their anti-cancer activities against four different types of cancer cells. Compound 9a exhibited the highest anti-cancer activity against human liver tumor cells Huh-7 and HepG2, with corresponding half-inhibitory concentration (IC50) values of 12.82 and 23.37 micrometers, respectively, and high tumor selectivity ratios of 16.91 and 9.28, respectively, compared to 5-fluorouracil. Cell cycle analysis revealed that compound 9a was able to inhibit cell proliferation in both the G0/G1 and G2/M phases of the cell cycle distribution. The effect of compound 9a derivatives on the expression levels of five tumor-regulating genes was investigated, showing significant downregulation of Caspase-9, p21, and Bcl-2 gene expression, as well as regulation of p53 and BAX gene expression, as assessed by quantitative RT-PCR analysis. The therapeutic effectiveness of compound (9a) has been proven in treating chemically induced liver cancer in experimental rats with diethylnitrosamine (DEN) over the course of 35 days of treatment with the compound, and its therapeutic effectiveness was compared to the effectiveness of the compound currently used in treatment for humans, which is sorafenib. This conclusion was reached based on the results of tissue analysis (Histopathology), which showed viable clusters of tumor tissue composed of malignant liver cells that did not show any detectable mitotic forms, with evidence of regression in the form of fibrosis and their replacement by normal, regenerating liver cells, which indicates near complete pathological response to therapy. Rats injected with DEN also experienced liver enlargement, oxidative stress, high levels of liver enzymes, low albumin, and high levels of the tumor marker alpha-protein (AFP). Gene expression analysis showed that compound (9a) attenuated DEN-induced changes in the investigated molecular markers by upregulating apoptosis marker (Cas-9) and downregulating markers of angiogenesis (VEGFR-2), tissue remodeling (MMP-9), regulation of the cell cycle (CcnD-1) and inflammation (IL-6, TNF-α, and TGFβ-1).