Sipholane triterpenoids: chemistry, reversal of ABCB1/P-glycoprotein-mediated multidrug resistance, and pharmacophore modeling.
This study reports the isolation of nine new terpenoids (2-10), possessing two novel skeletons, from the Red Sea sponge Callyspongia (=Siphonochalina) siphonella. The identity of these novel skeletons was based on X-ray crystallography and extensive spectral analyses. These compounds were evaluated for their ability to reverse P-glycoprotein (P-gp)-mediated multidrug resistance in human epidermoid cancer cells. Sipholenone E (3) was better than sipholenol A (1), a known P-gp modulator from this sponge, in reversing the P-gp-mediated multidrug resistance. Sipholenol L (6) and siphonellinol D (8) were nearly as active as sipholenol A. On the basis of X-ray crystallographic data and the established identity of 3-7, the structure of sipholenol I (11) is revised. A pharmacophore model of three hydrophobic points and two H-bond acceptors was generated for the active sipholane P-gp modulators.
Jain
Sandeep
S
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana, Monroe, LA 71201, USA.
Abraham
Ioana
I
Carvalho
Paulo
P
Kuang
Ye-Hong
YH
Shaala
Lamiaa A
LA
Youssef
Diaa T A
DT
Avery
Mitchell A
MA
Chen
Zhe-Sheng
ZS
El Sayed
Khalid A
KA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects*; D000818:Animals; D047128:Callyspongia / Q000737:chemistry*; D018360:Crystallography, X-Ray; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D019156:Indian Ocean; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014315:Triterpenes; C523549:sipholenol A