Yahui Ding

Guaianolide Sesquiterpene Lactones, a Source To Discover Agents That Selectively Inhibit Acute Myelogenous Leukemia Stem and Progenitor Cells

Small molecules that can selectively target cancer stem cells (CSCs) remain rare currently and exhibit no common structural features. Here we report a series of guaianolide sesquiterpene lactones (GSLs) and their derivatives that can selectively eradicate acute myelogenous leukemia (AML) stem or progenitor cells. Natural GSL compounds arglabin, an anticancer clinical drug, and micheliolide (MCL), are able to reduce the proportion of AML stem cells (CD34⁺CD38⁻) in primary AML cells. Targeting of AML stem cells is further confirmed by a sharp reduction of colony-forming units of primary AML cells upon MCL treatment. Moreover, DMAMCL, the dimethylamino Michael adduct of MCL, slowly releases MCL in plasma and in vivo and demonstrates remarkable therapeutic efficacy in the nonobese diabetic/severe combined immunodeficiency AML models. These findings indicate that GSL is an ample source for chemical agents against AML stem or progenitor cells and that GSL is potentially highly useful to explore anti-CSC approaches.

Protection-group-free semisyntheses of parthenolide and its cyclopropyl analogue.

Parthenolide showed extensive bioactivities including selective eradication of AML stem cells. Herein we report protection-free semisyntheses of parthenolide and its cyclopropyl analogue (compound 10) from the abundant natural product costunolide with an overall yield of 55 and 60%, respectively. Compound 10 was more stable than parthenolide, and it maintained comparable activities against AML cell lines and AML stem cells. Therefore, compound 10 might be a superior small molecule than parthenolide as a tool for investigation of cancer stem cell biology.

Syntheses and biological evaluation of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib

Three novel series of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib were prepared and evaluated in vitro for their cytostatic effects against a human chronic myeloid leukemia (K562), acute myeloid leukemia (HL60), and human leukemia stem-like cell line (KG1a). The structure-activity relationship was analyzed by determining the inhibitory rate of each imatinib analog. Benzene and piperazine rings were necessary groups in these compounds for maintaining inhibitory activities against the K562 and HL60 cell lines. Introducing a trifluoromethyl group significantly enhanced the potency of the compounds against these two cell lines. Surprisingly, some compounds showed significant inhibitory activities against KG1a cells without inhibiting common leukemia cell lines (K562 and HL60). These findings suggest that these compounds are able to inhibit leukemia stem-like cells.

Total Synthesis of Tubulysin U and Its C‐4 Epimer

The Tup fragments of tubulysins were synthesized with a tandem reaction as the key step, and unexpected diastereoselectivity was observed in the first Grignard addition stage. The coupling of the enolate of a thiazolyl ketone with chiral sulfinimines furnished the backbone of the Tuv fragment with over 100:1 d.r. and high yield. Thus, tubulysin U and C-4 epi-tubulysin U were prepared in a highly selective and efficient manner. The results of the MTT assay furthermore indicated that C-4 epi-tubulysin U maintained significant growth inhibition activities against several cancer cell lines.

Synthesis of Micheliolide Derivatives and Their Activities against AML Progenitor Cells

Micheliolide (MCL) derivatives with etherification or esterification of the hydroxyl group at the C4 position were synthesized and evaluated for their activities against different acute myelogenous leukemia (AML) cell lines. These derivatives demonstrated comparable activities against AML cell lines HL-60 and doxorubicin resistant cell line HL-60/A. As to multi-drug resistant AML progenitor cells KG-1a, MCL and some of its derivatives maintained significant activities, and only 1.1–2.7 fold activity reductions were observed when compared with the activities against HL-60, while doxorubicin showed 20-fold activity reduction. Our study demonstrated that the C4 hydroxyl group of MCL might not only be a suitable position for structural modifications, but also be a starting point for the design of appropriate molecular probes to explore the specific targets in the progenitor cell line KG-1a.

The biomarkers of leukemia stem cells in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by morphology and chromosome aberrations with high mortality. Leukemia stem cells (LSCs) in AML played important roles in leukemia initiation, progression, and were considered to be the root of chemotherapeutic drug resistance and disease relapse. The identification and targeting LSCs depended on membrane markers like CD34, CD38, CD123, TIM3, CD25, CD32 and CD96. In addition, the transcription factors were also therapeutic targets in eradicating LSCs, such as histone deacetylases (HDACs), NF-κB, HIF-1α and β-catenin. Besides membrane markers and transcription factors, intracellular reactive oxygen species (ROS), telomerase and microRNAs were identified to be new targets for ablating LSCs in AML.

Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells

BackgroundThe poor outcomes for patients diagnosed with acute myeloid leukemia (AML) are largely attributed to leukemia stem cells (LSCs) which are difficult to eliminate with conventional therapy and responsible for relapse. Thus, new therapeutic strategies which could selectively target LSCs in clinical leukemia treatment and avoid drug resistance are urgently needed. However, only a few small molecules have been reported to show anti-LSCs activity.MethodsThe aim of the present study was to identify alantolactone as novel agent that can ablate acute myeloid leukemia stem and progenitor cells from AML patient specimens and evaluate the anticancer activity of alantolactone in vitro and in vivo.ResultsThe present study is the first to demonstrate that alantolactone, a prominent eudesmane-type sesquiterpene lactone, could specifically ablate LSCs from AML patient specimens. Furthermore, in comparison to the conventional chemotherapy drug, cytosine arabinoside (Ara-C), alantolactone showed superior effects of leukemia cytotoxicity while sparing normal hematopoietic cells. Alantolactone induced apoptosis with a dose-dependent manner by suppression of NF-kB and its downstream target proteins. DMA-alantolactone, a water-soluble prodrug of alantolactone, could suppress tumor growth in vivo.ConclusionsBased on these results, we propose that alantolactone may represent a novel LSCs-targeted therapy and eudesmane-type sesquiterpene lactones offer a new scaffold for drug discovery towards anti-LSCs agents.

Epothilone D and its 9-Methyl analogues: combinatorial syntheses, conformation, and biological activities.

Epothilone D (Epo D) and its 9-Methyl conformational analogues were synthesized through a highly efficient combinatorial approach. The fragment E was synthesized in 11 total steps with 6 longest linear steps, and each aldehyde B was prepared via a 3-step sequence. Starting from the common precursor E and a suitable aldehydes B, each target molecule were obtained in only 4 steps. The 9-(S)-epo D and 9-(R)-epo D demonstrated significant difference in inhibition activities against cancer cell lines and in conformational analysis.

Structure–Activity Relationship Study of Rakicidins: Overcoming Chronic Myeloid Leukemia Resistance to Imatinib with 4-Methylester-Rakicidin A

Natural product rakicidin A induces cell death in TKI-resistant chronic myelogenous leukemia (CML) cells. Therefore, 14 rakicidin A analogues were synthesized via a highly efficient combinatorial strategy and were evaluated against CML cell lines. The conjugated diene moiety was found to be crucial for the anti-CML activity of rakicidin A, and the changes in the configuration(s) at C-2, C-3, C-14, C-15, and C-16 resulted in lower levels of anti-CML activity. The most promising compound was 4-methylester rakicidin A (1a). Compared with rakicidin A, 1a exhibited 2.8-fold greater potency against the imatinib-resistant cell line K562/G(+) and approximately 100-fold enhanced potency compared with that of imatinib. Furthermore, compound 1a demonstrated a significantly lower resistance index against Ba/F3 cells expressing BCR-ABL(T315I) than bosutinib, dasatinib, nilotinib, and ponatinib, while 1a exhibited less effect on normal hematopoietic cells. Preliminary results indicated that 1a down-regulated caspase-3 and PARP, which contributes to its K562 cell inhibitory activity.

Total Syntheses and Biological Activities of Vinylamycin Analogues

Natural depsipeptide vinylamycin was reported to be an antibiotic previously. Herein we report vinylamycin to be active against K562 leukemia cells (IC50 = 4.86 μM) and be unstable in plasma (t1/2 = 0.54 h). A total of 24 vinylamycin analogues with modification of the OH group and chiral centers were generated via a combinatorial approach. The lead compound 1a was subsequently characterized as having the following: no antimicrobial activity, significantly higher plasma stability (t1/2 = 14.3 h), improved activity against K562 leukemia cells (IC50 = 0.64 μM), and up to 75% cell inhibition without significant toxicities in K562 cells xenograft zebrafish model. Furthermore, compound 1a maintained its activity against the breast cancer cell line MCF-7 under hypoxic conditions. In comparison, the activity of gemcitabine in the same hypoxic in vitro model of MCF-7 cells was 15-fold lower. Therefore, the present results demonstrate that 1a has great potential as an anticancer agent.