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Novel Active Homo-Aza (Lactam) Steroidal Antimetabolites for the Treatment of Human Pancreatic and Colorectal Cancer

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Τίτλος: Novel Active Homo-Aza (Lactam) Steroidal Antimetabolites for the Treatment of Human Pancreatic and Colorectal Cancer
Συγγραφείς: Konstantinos E. Alifieris, Panagiotis Dalezis, Sofia Sagredou, Ioanna A. Anastasiou, Maria Deligiorgi, Christos Siokatas, Nikolaos Spanakis, Konstantinos Almpanakis, Maria Voura, Kyriakos Orfanakos, Mihalis Panayiotidis, Vasiliki Sarli, Dimitrios T. Trafalis
Πηγή: Pharmaceuticals ; Volume 19 ; Issue 2 ; Pages: 331
Στοιχεία εκδότη: Multidisciplinary Digital Publishing Institute
Έτος έκδοσης: 2026
Συλλογή: MDPI Open Access Publishing
Θεματικοί όροι: colorectal neoplasms/drug therapy, pancreatic neoplasms/drug therapy, antimetabolites, antineoplastic/pharmacology, steroids/pharmacology, thymidylate synthase inhibitors/pharmacology, dihydrofolate reductase inhibitors/pharmacology, molecular docking simulation, structure–activity relationship, apoptosis/drug effects, homo-aza lactam steroidal conjugates
Περιγραφή: Background: Colorectal and pancreatic cancers remain therapeutically challenging, with limitations in efficacy and limitations due to toxicity from conventional antimetabolites such as 5-fluorouracil (5-FU), methotrexate (MTX), and gemcitabine (GEM). Steroidal conjugation offers an approach to enhance selectivity and toxicokinetics. Methods: Five novel hybrid homo-aza (lactam) steroidal antimetabolites (GE23, CS18, CS23, KA44, MV16) were synthesized and tested against three pancreatic and four colorectal carcinoma cell lines with distinct molecular characteristics. Antiproliferative activity (MTT), apoptosis (Annexin V/PI), and cell cycle effects were assessed. Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibition was examined via molecular docking, Western blot, and enzymatic assays. Correlations between docking binding scores (DBS) and biological data were analyzed, and effects were compared with reference drugs (5-FU, MTX, GEM). Results: CS23, CS18, and KA44 exhibited the most potent cytostatic activity (mean GI50 10–80 µM). CS23 also induced high cytocidal effects, strong apoptosis (40% at 72 h), and G1/S arrest. Moreover, docking predicted the high binding affinity of CS23 for both TS (−11.2 kcal/mol) and DHFR (−11.5 kcal/mol), which was validated by Western blot and enzymatic inhibition (IC50 ≈ 20 nM). Correlation analyses showed significant relationships between hybrid steroidal antimetabolites’ cytostatic efficacy and DBS for TS (r = −0.75) and DHFR (r = −0.76), and combined DBS values predicted growth inhibition (r = −0.81, p < 0.01). No simple, universal correlation with single mutations of KRAS, BRAF, PI3K, or TP53 was found. Conclusions: Lactam steroidal antimetabolite hybrids, particularly CS23, act as dual TS/DHFR inhibitors, inducing apoptosis and cell cycle arrest with improved selectivity. Their strong in silico–in vitro concordance provides a compelling preclinical rationale for further evaluation of steroidal antimetabolites as next-generation therapeutics for resistant ...
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Γλώσσα: English
Relation: Medicinal Chemistry; https://dx.doi.org/10.3390/ph19020331
DOI: 10.3390/ph19020331
Διαθεσιμότητα: https://doi.org/10.3390/ph19020331
Rights: https://creativecommons.org/licenses/by/4.0/
Αριθμός Καταχώρησης: edsbas.7E85ECFF
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  Data: Novel Active Homo-Aza (Lactam) Steroidal Antimetabolites for the Treatment of Human Pancreatic and Colorectal Cancer
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  Data: &lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Konstantinos+E%2E+Alifieris%22&quot;&gt;Konstantinos E. Alifieris&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Panagiotis+Dalezis%22&quot;&gt;Panagiotis Dalezis&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Sofia+Sagredou%22&quot;&gt;Sofia Sagredou&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Ioanna+A%2E+Anastasiou%22&quot;&gt;Ioanna A. Anastasiou&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Maria+Deligiorgi%22&quot;&gt;Maria Deligiorgi&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Christos+Siokatas%22&quot;&gt;Christos Siokatas&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Nikolaos+Spanakis%22&quot;&gt;Nikolaos Spanakis&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Konstantinos+Almpanakis%22&quot;&gt;Konstantinos Almpanakis&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Maria+Voura%22&quot;&gt;Maria Voura&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Kyriakos+Orfanakos%22&quot;&gt;Kyriakos Orfanakos&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Mihalis+Panayiotidis%22&quot;&gt;Mihalis Panayiotidis&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Vasiliki+Sarli%22&quot;&gt;Vasiliki Sarli&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Dimitrios+T%2E+Trafalis%22&quot;&gt;Dimitrios T. Trafalis&lt;/searchLink&gt;
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  Data: Pharmaceuticals ; Volume 19 ; Issue 2 ; Pages: 331
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  Data: Multidisciplinary Digital Publishing Institute
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  Data: 2026
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  Data: &lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22colorectal+neoplasms%2Fdrug+therapy%22&quot;&gt;colorectal neoplasms/drug therapy&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22pancreatic+neoplasms%2Fdrug+therapy%22&quot;&gt;pancreatic neoplasms/drug therapy&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22antimetabolites%22&quot;&gt;antimetabolites&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22antineoplastic%2Fpharmacology%22&quot;&gt;antineoplastic/pharmacology&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22steroids%2Fpharmacology%22&quot;&gt;steroids/pharmacology&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22thymidylate+synthase+inhibitors%2Fpharmacology%22&quot;&gt;thymidylate synthase inhibitors/pharmacology&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22dihydrofolate+reductase+inhibitors%2Fpharmacology%22&quot;&gt;dihydrofolate reductase inhibitors/pharmacology&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22molecular+docking+simulation%22&quot;&gt;molecular docking simulation&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22structure–activity+relationship%22&quot;&gt;structure–activity relationship&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22apoptosis%2Fdrug+effects%22&quot;&gt;apoptosis/drug effects&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22homo-aza+lactam+steroidal+conjugates%22&quot;&gt;homo-aza lactam steroidal conjugates&lt;/searchLink&gt;
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  Data: Background: Colorectal and pancreatic cancers remain therapeutically challenging, with limitations in efficacy and limitations due to toxicity from conventional antimetabolites such as 5-fluorouracil (5-FU), methotrexate (MTX), and gemcitabine (GEM). Steroidal conjugation offers an approach to enhance selectivity and toxicokinetics. Methods: Five novel hybrid homo-aza (lactam) steroidal antimetabolites (GE23, CS18, CS23, KA44, MV16) were synthesized and tested against three pancreatic and four colorectal carcinoma cell lines with distinct molecular characteristics. Antiproliferative activity (MTT), apoptosis (Annexin V/PI), and cell cycle effects were assessed. Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibition was examined via molecular docking, Western blot, and enzymatic assays. Correlations between docking binding scores (DBS) and biological data were analyzed, and effects were compared with reference drugs (5-FU, MTX, GEM). Results: CS23, CS18, and KA44 exhibited the most potent cytostatic activity (mean GI50 10–80 &#181;M). CS23 also induced high cytocidal effects, strong apoptosis (40% at 72 h), and G1/S arrest. Moreover, docking predicted the high binding affinity of CS23 for both TS (−11.2 kcal/mol) and DHFR (−11.5 kcal/mol), which was validated by Western blot and enzymatic inhibition (IC50 ≈ 20 nM). Correlation analyses showed significant relationships between hybrid steroidal antimetabolites’ cytostatic efficacy and DBS for TS (r = −0.75) and DHFR (r = −0.76), and combined DBS values predicted growth inhibition (r = −0.81, p &lt; 0.01). No simple, universal correlation with single mutations of KRAS, BRAF, PI3K, or TP53 was found. Conclusions: Lactam steroidal antimetabolite hybrids, particularly CS23, act as dual TS/DHFR inhibitors, inducing apoptosis and cell cycle arrest with improved selectivity. Their strong in silico–in vitro concordance provides a compelling preclinical rationale for further evaluation of steroidal antimetabolites as next-generation therapeutics for resistant ...
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  Data: Medicinal Chemistry; https://dx.doi.org/10.3390/ph19020331
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