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1.
Oncol Nurs Forum ; 41(3): 327-30, 2014 May.
Article in English | MEDLINE | ID: mdl-24769598

ABSTRACT

A 58-year-old man named J.S. was diagnosed with non-Hodgkin lymphoma and underwent treatment with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. He presented to his local outpatient clinic for evaluation and laboratory tests on day 10 after cycle 3. During this visit, J.S. reported great difficulty opening his mouth with significant gingival and lingual pain when eating and drinking in spite of prophylactic oral care. Laboratory test results revealed a white blood cell count of 0.9 k/ul, hemoglobin level of 8.9 g/dl, platelets of 100 k/ul, serum creatinine level of 1 mg/dl, and blood urea nitrogen level of 29 mg/dl.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antiviral Agents/therapeutic use , Herpes Simplex/virology , Lymphoma, Non-Hodgkin/drug therapy , Stomatitis/virology , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Humans , Male , Middle Aged , Prednisone/administration & dosage , Prednisone/adverse effects , Rituximab , Stomatitis/drug therapy , Vincristine/administration & dosage , Vincristine/adverse effects
2.
Chem Biol Drug Des ; 76(1): 17-24, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20492447

ABSTRACT

In our recent studies, we focused our attention on the synthesis of several gamma-hydroxybutenolides designed on the basis of petrosaspongiolide M 1 (PM) structure that has been recognized to potently inhibit the inflammatory process through the selective PLA(2) enzyme inhibition. By means of a combination of computational methods and efficient synthetic strategies, we generated small collections of PM modified analogs to identify new potent PLA(2) inhibitors, suitable for clinical development. In the course of the biological screening of our compounds, we discovered a potent and selective inhibitor of mPGES-1 expression, the benzothiophene gamma-hydroxybutenolide 2, which so far represents the only product, together with resveratrol, able to reduce PGE(2) production through the selective downregulation of mPGES-1 enzyme. In consideration that microsomal prostaglandin E synthase 1 (mPGES-1) is one of the most strategic target involved both in inflammation and in carcinogenesis processes, we decided to explore the biological effects of some structural changes of the gamma-hydroxybutenolide 2, hoping to improve its biological profile. This optimization process led to the identification of three strictly correlated compounds 14g, 16g, and 18 with higher inhibitory potency on PGE(2) production on mouse macrophage cell line RAW264.7 through the selective modulation of mPGES-1 enzyme expression.


Subject(s)
4-Butyrolactone/analogs & derivatives , Gene Expression/drug effects , Intramolecular Oxidoreductases/antagonists & inhibitors , Intramolecular Oxidoreductases/genetics , Microsomes/drug effects , Thiophenes/chemistry , Thiophenes/pharmacology , 4-Butyrolactone/chemistry , 4-Butyrolactone/pharmacology , Animals , Cell Line , Cyclooxygenase 2/genetics , Dinoprostone/metabolism , Drug Discovery , Intramolecular Oxidoreductases/metabolism , Macrophages/drug effects , Macrophages/enzymology , Mice , Microsomes/enzymology , Oleanolic Acid/analogs & derivatives , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Prostaglandin-E Synthases
3.
Bioorg Med Chem ; 16(19): 9056-64, 2008 Oct 01.
Article in English | MEDLINE | ID: mdl-18790649

ABSTRACT

Petrosaspongiolide M (PM), a marine sesterterpene metabolite bearing the gamma-hydroxybutenolide scaffold and displaying a potent inhibitory activity toward PLA(2) enzyme, was selected by us as an attractive target in order to explore its mechanism of action at molecular level. In the course of our investigations we decided to synthetically modify the parent compound to clarify the structural determinants responsible for the activity; in fact, very recently, our research group reported the synthesis and the pharmacological properties of a first collection of PM analogues generated by Ludi approach. The synthesized compounds showed a poor or moderate activity toward PLA(2) enzymes, nevertheless we discovered a potent and selective modulator of the expression of microsomal prostaglandin E synthase 1 (mPGES-1), an enzyme highly involved in the inflammatory response, which represents an interesting target for the development of a new class of anti-inflammatory agents. In this paper we report the synthesis of a further collection of nine analogues, having the same scaffold of PM, the gamma-hydroxybutenolide, and bearing, as side chain, more complex aromatic portions, in substitution of the sesterterpene moiety. Their pharmacological behavior against PLA(2) enzymes as well as to modulate the expression of inducible cyclooxygenase 2 (COX-2) and mPGES-1 enzymes is also described.


Subject(s)
4-Butyrolactone/metabolism , Anti-Inflammatory Agents/pharmacology , Enzyme Inhibitors/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Macrophages/drug effects , Microsomes/drug effects , Prostaglandin Antagonists/pharmacology , 4-Butyrolactone/chemistry , Animals , Anti-Inflammatory Agents/chemical synthesis , Binding Sites , Cell Line , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Enzyme Inhibitors/chemical synthesis , Gene Expression Regulation , Macrophages/metabolism , Mice , Microsomes/enzymology , Phospholipases A2/chemistry , Phospholipases A2/metabolism , Prostaglandin Antagonists/chemical synthesis , Prostaglandin-E Synthases , Structure-Activity Relationship
4.
J Med Chem ; 50(9): 2176-84, 2007 May 03.
Article in English | MEDLINE | ID: mdl-17407277

ABSTRACT

As a part of our drug discovery effort, recently we clarified the molecular basis of phospholipase A2 (PLA2) inactivation by petrosaspongiolide M (PM), an interesting metabolite belonging to a marine sesterterpene family, containing in its structural architecture a gamma-hydroxybutenolide moiety and showing potent anti-inflammatory activity. In the attempt to expand structural diversity as well as to simplify crucial synthetic features of the parent compound, we decided to develop a selected library based on the densely functionalized gamma-hydroxybutenolide scaffold. The synthesized products were tested for their ability to inhibit PLA2 enzymes as well as to modulate the expression of inducible cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1), two key enzymes highly involved in the inflammatory event, in order to discover new promising anti-inflammatory agents with better pharmacological profiles. This led us to the discovery of a promising inhibitor (4e) of prostanoid production acting by in vitro and in vivo selective modulation of microsomal prostaglandin E synthase 1 expression.


Subject(s)
4-Butyrolactone/analogs & derivatives , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Furans/chemical synthesis , Intramolecular Oxidoreductases/antagonists & inhibitors , Microsomes/enzymology , Prostaglandin Antagonists/chemical synthesis , Thiophenes/chemical synthesis , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , 4-Butyrolactone/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cell Line , Combinatorial Chemistry Techniques , Cyclooxygenase 2/biosynthesis , Dinoprostone/biosynthesis , Female , Furans/chemistry , Furans/pharmacology , Humans , Mice , NF-kappa B/metabolism , Phospholipases A/antagonists & inhibitors , Phospholipases A2 , Prostaglandin Antagonists/chemistry , Prostaglandin Antagonists/pharmacology , Prostaglandin-E Synthases , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacology
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