Thiothalidomides

Novel Isosteric Analogues of Thalidomide with Enhanced TNF-α Inhibitory Activity

Xiaoxiang Zhu, Tony Giordano, Qian Sheng Yu, Harold W. Holloway, Tracy Ann Perry, Debomoy Lahiri, Arnold Brossi, Nigel H. Greig

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Thalidomide is being increasingly used in the clinical management of a wide spectrum of immunologically-mediated and infectious diseases, and cancers. However, the mechanisms underlying its pharmacological action are still under investigation. In this regard, oral thalidomide is clinically valuable in the treatment of erythema nodosum leprosum (ENL) and mutiple myeloma and effectively reduces tumor necrosis factor-α (TNF-α) levels and angiogenesis in vivo. This contrasts with its relatively weak effects on TNF-α and angiogenesis in in vitro studies and implies that active metabolites contribute to its in vivo pharmacologic action and that specific analogues would be endowed with potent activity. Our focus in the structural modification of thalidomide is toward the discovery of novel isosteric active analogues. In this regard, a series of thiothalidomides and analogues were synthesized and evaluated for their TNF-α inhibitory activity against lipopolysacharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC), This was combined with a PBMC viability assay to differentiate reductions in TNF-α secretion from cellular toxicity. Two isosteric analogues of thalidomide, compounds 15 and 16, that mostly reflect the parent compound, together with the simple structure, dithioglutarimide 19, potently inhibited TNF-α secretion, compared to thalidomide, 1. The mechanism underpinning this most likely is posttranscriptional, as each of these compounds decreased TNF-α mRNA stability via its 3′-UTR. The potency of 19 warrants further study and suggests that replacement of the amide carbonyl with a thiocarbonyl may be beneficial for increased TNF-α inhibitory action. In addition, an intact phthalimido moiety appeared to be requisite for TNF-α inhibitory activity.

Original languageEnglish
Pages (from-to)5222-5229
Number of pages8
JournalJournal of Medicinal Chemistry
Volume46
Issue number24
DOIs
StatePublished - Nov 20 2003

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Thalidomide
Tumor Necrosis Factor-alpha
Blood Cells
Blood
Pharmacologic Actions
Erythema Nodosum
RNA Stability
3' Untranslated Regions
Metabolites
Amides
Communicable Diseases
Toxicity
Assays
Cell Survival
Pharmacology
Messenger RNA

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Thiothalidomides : Novel Isosteric Analogues of Thalidomide with Enhanced TNF-α Inhibitory Activity. / Zhu, Xiaoxiang; Giordano, Tony; Yu, Qian Sheng; Holloway, Harold W.; Perry, Tracy Ann; Lahiri, Debomoy; Brossi, Arnold; Greig, Nigel H.

In: Journal of Medicinal Chemistry, Vol. 46, No. 24, 20.11.2003, p. 5222-5229.

Research output: Contribution to journalArticle

Zhu, X, Giordano, T, Yu, QS, Holloway, HW, Perry, TA, Lahiri, D, Brossi, A & Greig, NH 2003, 'Thiothalidomides: Novel Isosteric Analogues of Thalidomide with Enhanced TNF-α Inhibitory Activity', Journal of Medicinal Chemistry, vol. 46, no. 24, pp. 5222-5229. https://doi.org/10.1021/jm030152f
Zhu, Xiaoxiang ; Giordano, Tony ; Yu, Qian Sheng ; Holloway, Harold W. ; Perry, Tracy Ann ; Lahiri, Debomoy ; Brossi, Arnold ; Greig, Nigel H. / Thiothalidomides : Novel Isosteric Analogues of Thalidomide with Enhanced TNF-α Inhibitory Activity. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 24. pp. 5222-5229.
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