Shama Nasim

Aminoparthenolides as novel anti-leukemic agents: Discovery of the NF-κB inhibitor, DMAPT (LC-1)

A series of aminoparthenolide analogs (6-37) were synthesized and evaluated for their anti-leukemic activity. Eight compounds exhibited good anti-leukemic activity with LD(50)s in the low microM range (1.5-3.0microM). Compounds 16, 24 and 30 were the most potent compounds in the series, causing greater than 90% cell death at 10microM concentration against primary AML cells in culture, with LD(50) values of 1.7, 1.8 and 1.6microM.

Antileukemic activity of aminoparthenolide analogs.

A series of aminoparthenolide analogs have been synthesized through a diastereoselective conjugate addition of several primary and secondary amines to the alpha-methylene-gamma-butyrolactone function of the very lipophilic sesquiterpene lactone, parthenolide. Seventeen of the above amines derivatives were evaluated in a full panel of 60 cancer cell lines for anticancer activity. Compound 12, derived from tyramine, was found to be cytostatic as well as cytotoxic toward acute lymphoblastic leukemia cells (ALL, CCRF-CEM) at nanomolar concentrations, while the (R)-(1,2,3,4-tetrahydro-1-naphthyl)amino derivative 9 was found to be cytostatic toward human anaplastic large T-cell lymphoma (SR) cells at concentrations below 10 nM.

Melampomagnolide B: A new antileukemic sesquiterpene

Melampomagnolide B has been identified as a new antileukemic sesquiterpene. A biotin-conjugated derivative of melampomagnolide B was designed and synthesized in order to elucidate its mechanism of action. A study of the biochemical interactions of the biotin probe suggests that melampomagnolide B derives its remarkable selectivity for leukemic cells over normal hematopoietic cells from its unique ability to exploit biochemical differences between the two cell types.

3-O-Phosphate ester conjugates of 17-β-O-{1-[2-carboxy-(2-hydroxy-4-methoxy-3-carboxamido)anilido]ethyl}1,3,5(10)-estratriene as novel bone-targeting agents

A series of 3-O-phosphorylated analogs (4-10) of a novel bone-targeting estradiol analog (3) were synthesized after a thorough study of the reaction of 3 with a selection of phosphoryl chlorides under a variety of reaction conditions. Evaluation of these novel phosphate analogs for affinity for hydroxyapatite revealed that they bind with equal or higher affinity when compared to the bone tissue accumulator, tetracycline.

Discovery of 1,2,4-thiadiazolidine-3,5-dione analogs that exhibit unusual and selective rapid cell death kinetics against acute myelogenous leukemia cells in culture.

4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) was previously identified as an antileukemic agent exhibiting no evident toxicity toward normal hematopoietic cells. An SAR study has been carried out to examine the effect of varying the C-2 and C-4- substituents on the thiadiazolidinone ring of TDZD-8 on antileukemic activity. These studies resulted in the identification of more druglike analogs that exhibited comparable potency to TDZD-8 in killing acute myelogenous leukemia (AML) cells in culture. Surprisingly, the cell death kinetics induced by several of these novel analogs on MV-411 cells were extremely fast, with commitment to death occurring within 30 min. At a concentration of 10 μM, 3f (LD(50)=3.5 μM) completely eradicated cell viability of MV-411 cells within 2h, while analog 3e (LD(50)=2.0 μM) decimated cell viability within 30 min at a concentration of 10 μM and effectively abolished cell viability at 5 μM within 1-2h.

Improved and Scalable Synthetic Route to the Synthon 17-β-(2-Carboxyethyl)-1,3,5(10)-estratriene: An Important Intermediate in the Synthesis of Bone-Targeting Estrogens

An improved, highly scalable methodology for the multigram-scale preparation of an important synthon, 17-β-(2-carboxyethyl)-1,3,5(10)-estratriene, is described. Previous approaches have failed to provide useful quantities of the analytically pure product because of facile retro-Michael breakdown of the β-alkoxy carbonyl precursors during workup and isolation operations. The synthetic approach described herein has been designed specifically to sidestep this problematic breakdown process. This new scalable method of preparation overcomes a major hurdle in the exploration of structure–activity relationships centered around novel estradiol derivatives with bone-targeting properties and also provides a scalable process for subsequent developmental work.

(11R,13R)-13-(Tetra­lin-1-ylamino)-4,5-ep­oxy-11,13-dihydro­costunolide

The title compound [systematic name: (12R)-4,8-dimethyl-12-[(1′R)-1′,2′,3′,4′-tetrahydro-1′-naphthyl)aminomethyl]-3,14-dioxatricyclo[9.3.0.02,4]tetradec-7-en-13-one}, C25H33NO3, was formed from the reaction of (1R)-1-aminotetralin with parthenolide in methanolic solution. X-ray crystal structure analysis determined that the configuration of the new chiral center in the title compound was R.

(11R)-13-[2-(4-Hydroxy­phen­yl)ethyl­amino]-4,5-ep­oxy-11,13-dihydro­costunolide monohydrate

The title compound (systematic name: 12-{[2-(4-hydroxyphenyl)ethyl]aminomethyl}-4,8-dimethyl-3,14-dioxatricyclo[9.3.0.02,4]tetradec-7-en-13-one monohydrate), C23H31NO4·H2O, was obtained by the reaction of tyramine with parthenolide. The configuration of the new chiral center in the title compound is R, establishing the stereospecificity of the amination reaction. The water molecule is disordered over three positions; the site occupancy factors are 0.45, 0.40 and 0.15.