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1.
Sci Rep ; 14(1): 14674, 2024 06 25.
Article in English | MEDLINE | ID: mdl-38918539

ABSTRACT

Sphaeropsidins are iso-pimarane diterpenes produced by phytopathogenic fungi that display promising anticancer activities. Sphaeropsidin A, in particular, has been shown to counteract regulatory volume increase, a process used by cancer cells to avoid apoptosis. This study reports the hemi-synthesis of new lipophilic derivatives obtained by modifications of the C15,C16-alkene moiety. Several of these compounds triggered severe ER swelling associated with strong proteasomal inhibition and consequently cell death, a feature that was not observed with respect to mode of action of the natural product. Significantly, an analysis from the National Cancer Institute sixty cell line testing did not reveal any correlations between the most potent derivative and any other compound in the database, except at high concentrations (LC50). This study led to the discovery of a new set of sphaeropsidin derivatives that may be exploited as potential anti-cancer agents, notably due to their maintained activity towards multidrug resistant models.


Subject(s)
Endoplasmic Reticulum , Humans , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Cell Line, Tumor , Apoptosis/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Diterpenes/pharmacology , Diterpenes/chemistry , Abietanes/pharmacology , Abietanes/chemistry
2.
J Med Chem ; 67(12): 9950-9975, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38865195

ABSTRACT

To improve their aqueous solubility characteristics, water-solubilizing groups were added to some antiproliferative, rigidin-inspired 7-deazahypoxanthine frameworks after molecular modeling seemed to indicate that structural modifications on the C7 and/or C8 phenyl groups would be beneficial. To this end, two sets of 7-deazahypoxanthines were synthesized by way of a multicomponent reaction approach. It was subsequently determined that their antiproliferative activity against HeLa cells was retained for those derivatives with a glycol ether at the 4'-position of the C8 aryl ring system, while also significantly improving their solubility behavior. The best of these compounds were the equipotent 6-[4-(2-ethoxyethoxy)benzoyl]-2-(pent-4-yn-1-yl)-5-phenyl-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 33 and 6-[4-(2-ethoxyethoxy)benzoyl]-5-(3-fluorophenyl)-2-(pent-4-yn-1-yl)-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 59. Similarly to the parent 1, the new derivatives were also potent inhibitors of tubulin assembly. In treated HeLa cells, live cell confocal microscopy demonstrated their impact on microtubulin dynamics and spindle morphology, which is the upstream trigger of mitotic delay and cell death.


Subject(s)
Antineoplastic Agents , Cell Proliferation , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , HeLa Cells , Models, Molecular , Solubility , Structure-Activity Relationship , Tubulin/metabolism , Benzodiazepines/chemistry , Benzodiazepines/pharmacology
3.
ACS Med Chem Lett ; 14(10): 1434-1440, 2023 Oct 12.
Article in English | MEDLINE | ID: mdl-37849558

ABSTRACT

The SARS-CoV-2 main protease (Mpro) has been proven to be a highly effective target for therapeutic intervention, yet only one drug currently holds FDA approval status for this target. We were inspired by a series of publications emanating from the Jorgensen and Anderson groups describing the design of potent, non-peptidic, competitive SARS-CoV-2 Mpro inhibitors, and we saw an opportunity to make several design modifications to improve the overall pharmacokinetic profile of these compounds without losing potency. To this end, we created a focused virtual library using reaction-based enumeration tools in the Schrödinger suite. These compounds were docked into the Mpro active site and subsequently prioritized for synthesis based upon relative binding affinity values calculated by FEP+. Fourteen compounds were selected, synthesized, and evaluated both biochemically and in cell culture. Several of the synthesized compounds proved to be potent, competitive Mpro inhibitors with improved metabolic stability profiles.

4.
J Med Chem ; 66(8): 5397-5414, 2023 04 27.
Article in English | MEDLINE | ID: mdl-37026870

ABSTRACT

The C-20 oxime of progesterone, EIDD-036 (2), demonstrates neuroprotection and improved outcomes in animal models of traumatic brain injury (TBI). However, 2 suffers from poor solubility, which renders it unsuitable for rapid administration. Previous prodrugs of 2 aimed at improving solubility by incorporating enzymatically labile amino acid and phosphate ester promoieties. These approaches were effective but led to limitations with in vivo administration. Herein, we disclose a pH-responsive water-soluble prodrug strategy to improve exposure to 2 through enzyme-independent activation. Compound 13l was identified as a lead that exhibits water-solubility, stability in acidic solutions, and rapid conversion to 2 at physiological pH. Administration of 13l to rats resulted in a twofold increase in exposure to 2 compared to the previous generation phosphate prodrug, EIDD-1723 (6). In a rat model of TBI, treatment with 13l resulted in a significant decrease in cerebral edema when administered postinjury.


Subject(s)
Brain Injuries, Traumatic , Prodrugs , Rats , Animals , Prodrugs/chemistry , Water/chemistry , Solubility , Phosphates/therapeutic use , Hydrogen-Ion Concentration , Brain Injuries, Traumatic/drug therapy
5.
Alkaloids Chem Biol ; 79: 191-220, 2018.
Article in English | MEDLINE | ID: mdl-29455836

ABSTRACT

Rigidins (2-6) are pyrrolopyrimidine alkaloids isolated from marine tunicates. Since their isolation, refinement of their total syntheses, and biochemical evaluation, interest toward this pyrrolo[2,3-d]pyrimidine scaffold as a medicinal candidate has been triggered. The derivatization of these natural products has led to the discovery of a novel range of 7-deazahypoxanthines, which exhibit extremely potent anticancer activity in human cancer cell lines. A major breakthrough toward the synthesis of rigidin and various rigidin analogues has been the application of multicomponent reactions (MCRs). The rapid assembly of molecular diversity and flexibility displayed by MCRs makes it an attractive strategy for the preparation of rigidin-inspired small molecules. Furthermore, a number of rigidin-like 7-deazaxanthine compounds have been reported in the literature and the popularity of implementing MCRs to construct these 7-deazaxanthines is highlighted here. It is our hope that the synthetic methods described in this chapter will result in the further generation of rigidin-inspired compounds that will move on from being "hits" into "leads" in the medicinal chemistry drug discovery pipeline and potentially into anticancer therapeutics.


Subject(s)
Alkaloids/chemical synthesis , Antineoplastic Agents/chemical synthesis , Chemistry Techniques, Synthetic/methods , Drug Discovery , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Alkaloids/isolation & purification , Alkaloids/pharmacology , Animals , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Aquatic Organisms/chemistry , Molecular Structure , Pyrimidines/isolation & purification , Pyrimidines/pharmacology , Pyrroles/isolation & purification , Pyrroles/pharmacology , Urochordata/chemistry
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