Nitric Ester Modified Saquinavir Antitumor Toxicity Reduction
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Solution Overview
Problem
HIV protease inhibitors, such as Saquinavir, exhibit adverse effects like hyper- or hypolipidaemia, cardiovascular diseases, diabetes, body fat redistribution, osteopenia, and osteoporosis, limiting their long-term use in cancer and HIV treatment, necessitating a reduction in toxicity and enhancement of efficacy.
Innovation Solution
The introduction of a nitric ester moiety to HIV protease inhibitors, specifically through the covalent attachment of NO to Saquinavir, Ritonavir, and Nelfinavir, using reaction with concentrated nitric acid in acetic anhydride/halogenated hydrocarbon at low temperatures, resulting in nitric esters with improved safety and efficacy profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If HIV protease inhibitors are used to treat tumors and HIV infections, then antitumor activity is achieved, but toxicity increases causing adverse effects such as hyper- or hypolipidaemia, cardiovascular diseases, diabetes, body fat redistribution, osteopenia and osteoporosis
Solution Approach 1:
The patent applies parameter changes by chemically modifying the parent HIV protease inhibitor molecules through esterification with nitric acid to form nitric esters. This chemical transformation changes the molecular structure and properties of the drug, resulting in compounds that maintain antitumor activity while reducing toxicity. The modification involves changing functional groups on the molecule to alter its biological interaction profile
Solution Approach 2:
The invention creates composite molecular structures by combining the core HIV protease inhibitor framework with nitric acid ester groups. This results in a hybrid compound (nitric ester of HIV protease inhibitor) that integrates the antitumor properties of the parent compound with the beneficial effects of nitric ester moieties, achieving both efficacy and reduced side effects
2Duration of action of stationary object
If the application of HIV protease inhibitors is continued for long-term use, then therapeutic effect is maintained, but adverse effects accumulate including hyper- or hypolipidaemia, cardiovascular diseases, diabetes, body fat redistribution, osteopenia and osteoporosis
Solution Approach 1:
The chemical modification of converting parent HIV protease inhibitors to their nitric ester derivatives changes the pharmacological parameters of the drug. This structural alteration modifies how the drug interacts with biological systems over time, reducing the accumulation of adverse effects during long-term therapy while preserving the therapeutic antitumor activity
3Adaptability or versatility
If conventional HIV protease inhibitors are used, then broad spectrum activity against HIV and tumor cells is achieved, but selectivity between tumor cells and normal cells decreases leading to systemic toxicity
Solution Approach 1:
The nitric ester modification introduces localized chemical changes to the HIV protease inhibitor molecules that alter their biological interactions. This local structural modification creates differences in how the modified compounds interact with tumor cells versus normal cells, enhancing selectivity and reducing systemic toxicity while maintaining the broad-spectrum antitumor activity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The nitric ester modification, particularly for Saquinavir (NO-saquinavir), demonstrates enhanced antitumor activity with reduced toxicity, showing superior cytostatic effects and minimal NO release, effectively targeting tumor cells while sparing normal cells, thus offering a promising therapeutic option for tumors and HIV infections.
Implementation Method 1
covalent attachment of NO
Implementation Method 2
The NO moiety is introduced on the hydroxy group present on the known protease inhibitors by conventional methods, i.e. by reaction with concentrated nitric acid in acetic anhydride/halogenated hydrocarbon at temperatures lower than 0°C
Data Source
Figure 1
Figure 2A~2C
Figure 3A~3B
AI summary
HIV-protease inhibitors, particularly saquinavir, showed strong anticancer activity but numerous side effects limited its application. In order to overcome its toxicity original compounds wewre modified by covalent attachment of NO. The efficacy of parental and NO-modified drug was compared in vitro and in vivo. Anticancer activities of NO-modified saquinavir (Saq-NO) was monitored in vitro using assay for cell viability, proliferation, necrotic, autophagic and apoptotic cell death, differentiation, expression of intracellular molecules such as cyclin D3, p53 and Akt. Antitumor properties and toxicity of the compound was estimated in vivo. Saq-NO abrogated the viability of large spectrum of human and rodent tumor cell lines with IC50 significantly lower than parental drug and expressed strong antimelanoma action in vivo. In contrast to saquinavir, there was no detectable toxicity against primary cells in vitro and in vivo. Saq-NO permanently diminished cell proliferation by induction of cell cycle block accompanied with minor presence of tumor cell death. Repressed proliferation was coordinated with strong activation of p53 and differentiation of C6 and B16 cells into oligodendrocytes or "Schwan" like cells, respectively. Oppositely to general characteristic of saquinavir to inhibit Akt signalling, Saq-NO treatment resulted in transient and intensive upregulation of Akt. This antagonism between parental and modified compound could be the crucial for switch of saquinavir from toxic to completely untoxic drug.