Yuanrong Cheng

Design, Synthesis and Biological Evaluation of Novel Rapamycin Benzothiazole Hybrids as mTOR Targeted Anti-cancer Agents.

The immunosuppressant drug rapamycin, was firstly identified as a mammalian target of rapamycin (mTOR) allosteric inhibitor, and its derivatives have been successfully developed as anti-cancer drugs. Therefore, finding rapamycin derivatives with better anti-cancer activity has been proved to be an effective way to discover new targeted anti-cancer drugs. In this paper, structure modification was performed at the C-43 position of rapamycin using bioisosterism and a hybrid approach: a series of novel rapamycin-benzothiazole hybrids 4a-e, 5a-c, and 9a, b have been designed, synthesized and evaluated for their anti-cancer activity against Caski, CNE-2, SGC-7901, PC-3, SK-NEP-1 and A-375 human cancer cell lines. Some of these compounds (4a-e, 9a, b) displayed good to excellent potency against the Caski and SK-NEP-1 cell line as compared with rapamycin. Compound 9b as the most active compound showed IC50 values of 8.3 (Caski) and 9.6 μM (SK-NEP-1), respectively. In addition, research on the mechanism showed that 9b was able to cause G1 phase arrest and induce apoptosis in the Caski cell line. Most importantly, it significantly decreased the phosphorylation of S6 ribosomal protein, p70S6K1 and 4EBP1, which indicated that 9b inhibited the cancer cell growth by blocking the mTOR pathway and may have the potential to become a new mTOR inhibitor.

Synthesis of Rapamycin Derivatives Containing the Triazole Moiety Used as Potential mTOR-Targeted Anticancer Agents.

Rapamycin, a potent antifungal antibiotic, was approved as immunosuppressant, and lately its derivatives have been developed into mTOR targeting anticancer drugs. Structure modification was performed at the C‐42 position of rapamycin, and a novel series of rapamycin triazole hybrids (4a–d, 5a–e, 8a–e, and 9a–e) was facilely synthesized via Huisgens reaction. The anticancer activity of these compounds was evaluated against the Caski, H1299, MGC‐803, and H460 human cancer cell lines. Some of the derivatives (8a–e, 9a–e) appeared to have stronger activity than that of rapamycin; however, 4a–d and 5a–e failed to show potential anticancer activity. Compound 9e with a (2,4‐dichlorophenylamino)methyl moiety on the triazole ring was the most active anticancer compound, which showed IC50 values of 6.05 (Caski), 7.89 (H1299), 25.88 (MGC‐803), and 8.60 μM (H460). In addition, research on the mechanism showed that 9e was able to cause cell morphological changes and to induce apoptosis in the Caski cell line. Most importantly, 9e can decrease the phosphorylation of mTOR and of its downstream key proteins, S6 and P70S6K1, indicating that 9e can effectively inhibit the mTOR signaling pathway. Thus, it may have the potential to become a new mTOR inhibitor against various cancers.

FIM-A, a phosphorus-containing sirolimus, inhibits the angiogenesis and proliferation of osteosarcomas.

The mTOR pathway is a central control of cell growth, proliferation, metabolism, and survival, and is deregulated in most cancers. Cancer cells are addicted to increased activity of mTOR kinase-mediated signaling pathways, leading to numerous inhibitors of mTOR signaling in preclinic and clinical trials for cancer therapy. Phosphorus-containing sirolimus (FIM-A), which targets mTOR signaling, inhibits cancer cell growth in vitro. Here we report that FIM-A reduces the angiogenesis and proliferation of osteosarcoma both in vitro and in vivo. In cultured osteosarcoma cell lines, FIM-A inhibited cell proliferation and arrested cells in the G1 phase of the cell cycle, accompanied with reduction of VEGF and HIF-1alpha. With in vivo mouse osteosarcoma xenografts, FIM-A treatment resulted in the inhibition of mTORC1 signaling as demonstrated by the decreased phosphorylation of p70S6K1 and 4E-BP1. Consistent with this finding, FIM-A significantly decreased the average tumor volume, nuclei staining of PCNA, and the number of intratumoral microvessels. Our data demonstrated that targeting mTORC1 by FIM-A inhibited the growth of osteosarcoma in vitro and in vivo, providing the basis for further development of FIM-A as a therapy for osteosarcoma patients.

41-Azido-41-de-oxy-rapamycin.

The title compound, C51H78N4O12, is a derivative of rapamycin, a triene macrolide antibiotic molecule isolated from Streptomyces hygroscopicus. The macrocyclic ring structure has 15 chiral centres, with one of the substituent hydroxy groups giving an intramolecular hydrogen bond to a ketone O-atom acceptor. The molecules also form intermolecular hydroxy–ketone O—H⋯O hydrogen-bonding associations, giving one-dimensional chains extending along (010). The crystal has 108 Å3 solvent-accessible voids.

40-De-oxy-40(S)-iodo-rapamycin.

The title compound, C51H78INO12, contains a 29-membered ring incorporating amide, lactone and ester groups. It contains a total of 15 stereogenic centres. In the crystal, molecules are linked by O—H⋯O hydrogen bonds, forming C(8) chains propagating in [100]. A weak intramolecular O—H⋯O interaction also occurs.

Synthesis and anticancer activity of novel rapamycin C-28 containing triazole moiety compounds

Rapamycin is an mTOR allosteric inhibitor with multiple functions such as immunosuppressive, anticancer, and lifespan prolonging activities. Its C‐43 semi‐synthetic derivatives temsirolimus and everolimus have been used as mTOR targeting anticancer drugs in the clinic. Following our previous research on antitumor rapalogs modified on the C‐43 position, 13 novel rapamycin triazole hybrids (6a–g, 7a–f) were designed and synthesized on the C‐28 position of rapamycin via Huisgens reaction. Anticancer assays indicated that the targeted derivatives containing phenyl and 4‐methylphenyl groups showed an obvious raise in anticancer activity. On the contrary, the compounds with methoxyl, amine, and halogen groups on the benzene ring displayed lower anticancer activity. Compound 6c, as the most active compound, showed a stronger inhibition effect as compared with rapamycin for almost all of the tested cell lines (p < 0.01), except PC‐3. Meanwhile, the effect of 6c on inducing apoptosis and cell cycle arrest in A549 cells was more powerful than that of rapamycin. In addition, 6c inhibited the phosphorylation of mTOR and its downstream key kinases 4EBP1 and p70S6K1 in A549 cells, indicating that 6c also effectively inhibits the mTORC1 signaling pathway as rapamycin. On the basis of these findings, 6c may have the potential to be developed as a new mTOR inhibitor against specific cancers.