Author: Pflum, Mary Kay H ; Dunworth, Matthew ; Al-Hamashi, Ayad A ; Knoff, Joseph R ; Dlamini, Samkeliso ; Casero, Robert A ; Alqahtani, Abdulateef ; Perera, Lalith ; Taylor, William R ; Rashid, Maisha S ; Tillekeratne, L M Viranga ; Koranne, Radhika ; Karaj, Endri

Despite the advances in treatment strategies, cancer is still the second leading cause of death in the USA. A majority of the currently used cancer drugs have limitations in their clinical use due to poor selectivity, toxic side effects and multiple drug resistance, warranting the development of new anticancer drugs of different mechanisms of action. Here we describe the design, synthesis and initial biological evaluation of a new class of antimitotic agents that modulate tubulin polymerization. Structurally, these compounds are chalcone mimics containing a 1-(1H-imidazol-2-yl)ethan-1-one moiety, which was initially introduced to act as a metal-binding group and inhibit histone deacetylase enzymes. Although several analogues selectively inhibited purified HDAC8 with IC₅₀ values in low micromolar range, tissue culture studies suggest that HDAC inhibition is not a major mechanism responsible for cytotoxicity. The compounds demonstrated cell growth inhibition with GI₅₀ values of upper nanomolar to low micromolar potency with significant selectively for cancer over normal cells. Interestingly, several compounds arrested HeLaM cells in mitosis and seem to target tubulin to cause mitotic arrest. For example, when combined with inhibitors of Aurora B kinase, they led to dramatic disassembly of the mitotic spindle. In-vitro tubulin polymerization studies showed that the compounds reduced the rate of polymerization of microtubules during the elongation phase and lowered the amount of polymerized tubulin during the plateau phase. Finally, in silico docking studies identified binding of IPE-7 to the colchicine site with similar affinity as the test compound D64131. These compounds represent a new antimitotic pharmacophore with limited HDAC inhibitory activity.

01 Jan 2020·FEBS LettersQ3 · BIOLOGY

Structural insights into the design of indole derivatives as tubulin polymerization inhibitors

Q3 · BIOLOGY

Article

Author: Yang, Jiazhen ; Li, Yuanyuan ; Yu, Yamei ; Li, Huijuan ; Hu, Daojun ; Niu, Lu ; Chen, Qiang ; Chen, Lijuan

Microtubules are composed of αβ‐tubulin heterodimers, and drugs that interfere with microtubule dynamics are used widely in cancer chemotherapy. Small synthetic molecules with an indole nucleus as a core structure have been identified as microtubule inhibitors and recognized as anticancer agents. However, structural information for the interactions between indole derivatives and tubulin is sparse. Here, we present the 2.55 Å crystal structure of tubulin in complex with the indole derivative D64131. We compare the binding modes of D64131, colchicine, and five other indole derivatives to tubulin. These results reveal the interactions between the indole derivatives and tubulin, explain previous results of structure‐activity‐relationship (SAR) studies and, thus, provide insights into the development of new indole derivatives targeting the colchicine binding site.

08 Oct 2009·Journal of Medicinal ChemistryQ1 · MEDICINE

Indolobenzazepin-7-ones and 6-, 8-, and 9-Membered Ring Derivatives as Tubulin Polymerization Inhibitors: Synthesis and Structure−Activity Relationship Studies

Q1 · MEDICINE

Article

Author: Putey, Aurélien ; Joseph, Benoît ; Kozielski, Frank ; Galmarini, Carlos M. ; Do, Quoc-Tuan ; Popowycz, Florence ; Talapatra, Sandeep K. ; Bernard, Philippe

Several small weight indole derivatives (D-64131, D-24851, BPR0L075, BLF 61-3, and ATI derivatives) are potent tubulin polymerization inhibitors and show nanomolar antiproliferative activity. Among them, indolobenzazepin-7-ones were recently disclosed as potent antimitotic agents. In an effort to improve this structure, we prepared new derivatives in order to evaluate their antiproliferative activity. 5,6,7,9-Tetrahydro-8H-indolo[2,3-e][3]benzazocin-8-one (1m) was found to be the most potent derivative inhibiting the cell growth of several cancer cell lines in the lower nanomolar range.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	DE	Baxter Oncology GmbH	-

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