Lipophilic Salirasib analogs with enhanced antiproliferative activity against human solid tumor cell lines

Aim: We proposed to determine the antiproliferative activity of a series of synthetic salirasib analogs, presenting or not a 1,2,3-triazole linker, against five different cancer cell lines. Results: Bioassay, cheminformatic, and in silico ADME-Tox allowed the identification of new potent analogs. SAR analysis allowed the identification of structural and physicochemical features that benefit the antiproliferative activity. Conclusion: Isoprenyl R chains with three or more isoprene units, or long aliphatic R chains are the preferred ones within the active compounds. Likewise, we have identified three compounds with better activity profiles than salirasib against all the cell lines tested.

Biological Profiling of Semisynthetic C19-Functionalized Ferruginol and Sugiol Analogues

The abietane-type diterpenoids are significant bioactive compounds exhibiting a varied range of pharmacological properties. In this study, the first synthesis and biological investigation of the new abietane-diterpenoid (+)-4-epi-liquiditerpenoid acid (8a) together with several of its analogs are reported. The compounds were generated from the readily available methyl callitrisate (7), which was obtained from callitrisic acid present in Moroccan Sandarac resin. A biological evaluation was conducted to determine the effects of the different functional groups present in these molecules, providing basic structure–activity relationship (SAR) elements. In particular, the ferruginol and sugiol analogs compounds 10–16 were characterized by the presence of a phenol moiety, higher oxidization states at C-7 (ketone), and the hydroxyl, methyl ester or free carboxylic acid at C19. The biological profiling of these compounds was investigated against a panel of six human solid tumor cell lines (HBL-100, A549, HeLa, T-47D, SW1573 and WiDr), four parasitic Leishmania species (L. donovani, L. infantum, L. guyanensis and L. amazonensis) and two malaria strains (3D7 and K1). Furthermore, the capacity of the compounds to modulate gamma-aminobutyric acid type A (GABAA) receptors (α1β2γ2s) is also described. A comparison of the biological results with those previously reported of the corresponding C18-functionalized analogs was conducted.

One-pot multicomponent green Hantzsch synthesis of 1,2-dihydropyridine derivatives with antiproliferative activity

A rapid route for obtaining unsymmetrical 1,2-dihydropyridines (1,2-DHPs) as opposed to 1,4-dihydropyridines (1,4-DHPs) has been achieved via a one-pot multicomponent Hantzsch reaction. A benign protocol has been developed for the preparation of various 1,2-dihydropyridine derivatives using heterogenized phosphotungstic acid on alumina support (40 wt %). High yields of over 75% have been accomplished in just 2–3.5 h after screening several heterogeneous catalysts and investigating the optimal reaction conditions. The catalyst chosen has passed the heterogeneity test and was shown to have the potential of being reused for up to 8 consecutive cycles before having a significant loss in activity. In addition, aromatic aldehydes gave the aforementioned regioisomer while the classical 1,4-DHPs were obtained when carrying out the reaction using aliphatic aldehydes. The preliminary study of the antiproliferative activity against human solid tumor cells demonstrated that 1,2-DHPs could inhibit cancer cell growth in the low micromolar range.

Discovery of 12O—A Novel Oral Multi-Kinase Inhibitor for the Treatment of Solid Tumor

A novel series of pyrimidine-benzotriazole derivatives have been synthesized and evaluated for their anticancer activity against human solid tumor cell lines. The most promising molecule 12O was identified for its excellent antiproliferative activities, especially against the SiHa cell line with IC50 value as 0.009 μM. Kinase inhibition assay assessed 12O was a potential multi-kinase inhibitor, which possessed potent inhibitory activities against cyclin-dependent kinases (CDKs) and fms-like tyrosine kinase (FLT) with IC50 values in the nanomolar range. Molecular docking studies illustrated that the introduction of triazole moiety in 12O was critical for CDKs inhibition. In addition, 12O inhibited cancer cell proliferation, colony-formation, and cell cycle progression and provoked apoptotic death in vitro. In an SiHa xenograft mouse model, a once-daily dose of compound 12O at 20 mg/kg significantly suppressed the tumor growth without obvious toxicity. Taken together, 12O provided valuable guide for further structural optimization for CDKs and FLT inhibitors.

587 Tumor-activated Fc-engineered anti-CTLA-4 monoclonal antibody, XTX101, demonstrates tumor-selective PD and efficacy in preclinical models

BackgroundThe clinical benefit of CTLA-4 blockade to cancer patients has been well established. However, the promising antitumor activity shown by anti-CTLA-4 monoclonal antibodies (mAb) has been limited by the occurrence of immune-mediated adverse reactions, especially when CTLA-4 inhibition is used in combination with anti-PD-1 therapy. These dose-limiting toxicities restrict the therapeutic use of CTLA-4 blockade. To overcome these limitations, we have developed a potent anti-CTLA-4 antibody that is selectively active in the tumor microenvironment (TME). This antibody is engineered with an Fc region for enhanced FcγR binding and peptides that mask antigen-binding regions. The masking peptides are designed to be selectively cleaved and released by proteases that are more active in the TME, resulting in restoration of full activity of the antibody in the TME.MethodsA novel, fully-humanized anti-huCTLA-4 mAb was shown to bind human CTLA-4 with improved affinity compared to ipilimumab, as measured by SPR. Engineering of the Fc region enhanced FcγR binding and ADCC function. In addition, CDR-binding peptides identified by phage display were covalently linked to the antibody using a protease-sensitive polypeptide linker. This engineered anti-CTLA-4 antibody (XTX101) showed protease-dependent binding to CTLA-4 both with recombinant and tumor tissue derived proteases.ResultsXTX101 demonstrated a 100-fold reduction in binding to human CTLA-4 by ELISA, compared to the non-masked antibody. Incubation with recombinant protease led to cleavage and release of the masking peptides and restored full binding to CTLA-4. Similarly, in vitro ADCC activity was impaired by masking and restored in a protease-dependent manner. SEB-stimulated human PMBCs were minimally responsive in vitro to XTX101, whereas PBMCs treated with proteolytically-activated XTX101 exhibited robust activation of T cell function. In human CTLA-4 knock-in mice with syngeneic MB49 tumors, XTX101 treatment led to complete tumor regression, enhanced CD8+ T cell proliferation, and depletion of tumor Tregs in the TME. By contrast, XTX101 had minimal pharmacodynamic effects in the periphery. In addition, XTX101 is effectively activated in culture supernatants from human solid tumor explants obtained from a broad range of tumor types.ConclusionsXTX101 is a tumor-selective anti-CTLA-4 mAb capable of: 1) effective CTLA-4 blockade, 2) depletion of intratumoral Tregs through enhanced antibody-dependent cellular cytotoxicity (ADCC) function, 3) minimization of systemic immune cell activation, and 4) potent anti-tumor activity. These pre-clinical data support the further evaluation of XTX101 in clinical studies.

Antiproliferative Activity and Effect on GABAA Receptors of Callitrisic Acid Derivatives

The semisynthesis and biological activity of the naturally occurring abietane diterpenoids callitrisic acid (4a; 4-epidehydroabietic acid) and callitrisinol (6) are reported. These compounds and jiadifenoic acid C (5) were obtained from methyl callitrisate (4b) isolated from Sandarac resin for biological evaluation and comparison with the biological activities of C4 epimers such as dehydroabietic acid (2a). In particular, the antiproliferative activity against a panel of six representative human solid tumor cell lines (A549, HBL-100, HeLa, SW1573, T-47D, WiDr) and the effect on GABAA receptors (α 1 β 2 γ 2s) were evaluated. The GI50 values were in the range of 3.4–61 µM and the potentiation of IGABA was 269–311% at 100 µM. Callitrisinol (6) was found to be 6.7-fold more potent than the reference etoposide in the WiDr (colon) cancer cell line. The role of the stereogenic center at C4 for antiproliferative and GABAA receptor modulating activities in the dehydroabietane scaffold has thus been revealed.

Cytotoxic and Antitumor Activity of some Coumarin Derivatives

Several natural and synthetic coumarins were assayed against different cancer cell lines. Four of them have shown cytotoxicity against a panel of three human solid tumor cell lines (HeLa, T-47D, and WiDr) and a clearly activity/hydrophobicity relationship. Compound 13 proved to be the most active product in all cell lines tested, with values of 8.0 (±0.38) μM against HeLa cells and also able to inhibit Taq DNA polymerase. This dual activity of 13 makes it a candidate to be considered as a “lead” compound in the search for novel antitumor drugs.