Synthesis and matrix metalloproteinase (MMP)-12 inhibitory activity of ageladine A and its analogs

Ageladine A (1) and its analogs 2-10 were expeditiously synthesized by featuring the biosynthetic route proposed for 1 (for 1-10) and by employing 2-(N-t-butoxycarbonylamino)imidazol-4-carbaldehyde as the starting material (for 1-8). From MMP-12 inhibitory activity assay, it appeared evident that the two bromine atoms and the three NH groups (1-NH, 14-NH, and 15-NH2) were indispensable for 1 to exhibit excellent activity.     

Synthesis and evaluation of biological activities of vibsanin A analogs

Vibsanin A is an 11-membered vibsane diterpenoid and is reported to induce myeloid cell differentiation via activation of protein kinase C (PKC) without tumor-promoting activity. Therefore, vibsanin A is thought to be an attractive compound for acute myeloid leukemia (AML) therapy. In this study, we synthesized vibsanin A analogs and compared the activity of these compounds for PKC activation and myeloid cell differentiation. We found that the hydroxymethyl group in vibsanin A is an important substituent to induce differentiation of AML cells. Collectively, our results showed the biochemical features of vibsanin A and provided new insights into the development of new antileukemic drugs.     

Synthesis and antifungal activities of miltefosine analogs

Miltefosine is an alkylphosphocholine that shows broad-spectrum in vitro antifungal activities and limited in vivo efficacy in mouse models of cryptococcosis. To further explore the potential of this class of compounds for the treatment of systemic mycoses, nine analogs (3a?3i) were synthesized by modifying the choline structural moiety and the alkyl chain length of miltefosine. In vitro testing of these compounds against the opportunistic fungal pathogens Candida albicans, Candida glabrata, Candida krusei, Aspergillus fumigatus, and Cryptococcus neoformans revealed that N-benzyl-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3a), N,N-dimethyl-N-(4-nitrobenzyl)-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3d), and N-(4-methoxybenzyl)-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3e) exhibited minimum inhibitory concentrations (MIC) of 2.5–5.0 μg/mL against all tested pathogens, when compared to miltefosine with MICs of 2.5–3.3 μg/mL. Compound 3a showed low in vitro cytotoxicity against three mammalian cell lines similar to miltefosine. In vivo testing of 3a and miltefosine against C. albicans in a mouse model of systemic infection did not demonstrate efficacy. The results of this study indicate that further investigation will be required to determine the potential usefulness of the alkylphosphocholines in the treatment of invasive fungal infections.     

Synthesis and antiproliferative activities of quebecol and its analogs

Simple and efficient synthesis of quebecol and a number of its analogs was accomplished in five steps. The synthesized compounds were evaluated for antiproliferative activities against human cervix adenocarcinoma (HeLa), human ovarian carcinoma (SK-OV-3), human colon carcinoma (HT-29), and human breast adenocarcinoma (MCF-7) cancer cell lines. Among all the compounds, 7c, 7d, 7f, and 8f exhibited antiproliferative activities against four tested cell lines with inhibition over 80% at 75 μM after 72 h, whereas, compound 7b and 7g were more selective towards MCF-7 cell line. The IC₅₀ values for compounds 7c, 7d, and 7f were 85.1 μM, 78.7 μM, and 80.6 μM against MCF-7 cell line, respectively, showing slightly higher antiproliferative activtiy than the synthesized and isolated quebecol with an IC₅₀ value of 104.2 μM against MCF-7.     

Synthesis of novel ageladine A analogs showing more potent matrix metalloproteinase (MMP)-12 inhibitory activity than the natural product

By employing a previously established synthetic scheme, the synthesis described in the title was carried out in order to explore the substituent effects in the pyrrole ring of ageladine A on MMP-12 inhibitory activity. It became evident that a halogen atom (Br or Cl) at the 2-position and an additional bromine atom at the 4-position are highly effective for improving the inhibitory activity. These studies led us to discover three novel ageladine A analogs (4a, c, o) showing more potent MMP-12 inhibitory activity than the natural product.     

Dehydrophenylalanyl analogs of bradykinin: Synthesis and biological activities

We have synthesized three analogs of the potent vasodilator peptide bradykinin, ArgProProGlyPhe SerProPheArg (BK), containing dehydrophenylalanine (Δ^zPhe) in place of the phenylalanyl residues at positions 5 and/or 8. The analogs, [Δ^zPhe⁵]BK, [Δ^zPhe⁸]BK, and [Δ^zPhe^5,8]BK, were assayed for their effects on isolated smooth muscle tissues and on the systemic arterial blood pressure of rats. In these assays [Δ^zPhe⁵]BK showed considerably high biological activities, particularly in terms of its blood pressure-lowering effects, being over 23 times more potent than BK when given intravenously. [Δ^zPhe⁸]BK was less potent than BK and [Δ^zPhe^5,8]BK had effects comparable to those of BK. All three synthetic analogs appear to be more resistant than BK to enzymic degradation during passage through the pulmonary vascular bed.     

Synthesis and structural analysis of oxadiazole carboxamide deoxyribonucleoside analogs

Two novel C-linked oxadiazole carboxamide nucleosides 5-(2'-deoxy-3',5'-beta-D-erythro-pentofuranosyl)-1,2,4-oxadiazole-5-carboxamide (1) and 5-(2'-deoxy-3',5'-beta-D-erythro-pentofuranosyl)-1,2,4-oxadiazole-3-carboxamide (2) were successfully synthesized and characterized by X-ray crystallography. The crystallographic analysis shows that both unnatural nucleoside analogs 1 and 2 adapt the C2'-endo ("south") conformation. The orientation of the oxadiazole carboxamide nucleobase moiety was determined as anti (conformer A) and high anti (conformer B) in the case of the nucleoside analog 1 whereas the syn conformation is adapted by the unnatural nucleoside 2. Furthermore, nucleoside analogs 1 and 2 were converted with high efficiency to corresponding nucleoside triphosphates through the combination chemo-enzymatic approach. Oxadiazole carboxamide deoxyribonucleoside analogs represent valuable tools to study DNA polymerase recognition, fidelity of nucleotide incorporation, and extension.     

Synthesis and anticancer activity of side chain analogs of the crambescidin alkaloids

Twenty three side chain analogs of the crambescidin alkaloids were prepared from the corresponding pentacyclic zwitterionic core acid. In the crambescidin 800 and 657 series, potency increased with increasing chain length. In addition, substantial variations in tumor selectivity with structure were seen. Crambescidin analogs having short, nonpolar side chains were identified for the first time as promising anticancer agents.     

3,4-Disubstituted oxazolidin-2-ones as constrained ceramide analogs with anticancer activities

Heterocyclic analogs of ceramide as 3-alkanoyl or benzoyl-4-(1-hydroxy-2-enyl)-oxazolidin-2-ones were designed by binding of primary alcohol and amide in sphinogosine backbone as a carbamate. They were synthesized by addition of acyl halide to the common ring 4-(1-t-butyldimethylsilyloxyhexadec-2-enyl)-oxazolidin-2-one which was elaborated from chiral aziridine-2-carboxylate including stereoselective reduction and ring opening reactions as key steps. Other analogs with different carbon frame at C4 position which is corresponding to the sphingoid backbone were prepared from 3-cyclopentanecarbonyl-4-(1-t-butyldimethylsilyloxybut-2-enyl)-oxazolidin-2-one and straight and cyclic alkenes by cross metathesis. All compounds were tested as antileukemic drugs against human leukemia HL-60 cells. Many of them including propionyl, cyclopentanoyl and p-nitrobenzoyl-4-(1-hydroxyhexadec-2-enyl)-oxazolidin-2-ones showed better antileukemic activities than natural C2-ceramide with good correlation between cell death and DNA fragmentation. There is a drastic change of the activities by the carbon chain lengths at C4 position. Cytotoxicity was induced by caspase activation without significant accumulation of endogenous ceramide concentration or any perturbation of ceramide metabolism.     

Synthesis,characterization, and anticancer evaluation of novel 4-hydrazinothiazole analogs

Single-step synthesis of novel 4-hydrazinothiazole derivatives 6a–e was achieved under mild conditions using the sequential four-components method involving isothiocyanate, aminoguanidine, carbonyl adduct, and α-haloketone derivatives. Deprotection of these hydrazinothiazoles was influenced by acylation, providing a novel group of diacylated molecular structures with a broader scope for the design of thiazolyl-containing drugs 7a and 7b . FTIR, ¹H/¹³C NMR, LC–MS spectroscopy, and CHN elemental analyses were used to study the compound chemical structures. Using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on human periodontal ligament fibroblast (HPDLF) cells, the 4-hydrazinothiazole derivatives were screened for cytotoxicity in an in vitro cytotoxicity investigation. The 4-hydrazinothiazole compound 6b bearing an isopropylidene-hydrazino group demonstrated strongly potent cytotoxicity against CAKI1 (IC₅₀ = 1.65 ± 0.24 μM) and A498 (IC₅₀ of 0.85 ± 0.24 μM). Furthermore, the chloroacetyl-containing thiazole compound 7a displayed efficient inhibition of growth against the test cell lines CAKI1 and A498 at low micromolar concentrations, IC₅₀ 0.78 and 0.74 μM, respectively.     

Synthesis of the A,B-ring-truncated OSW saponin analogs and their antitumor activities

The A,B-ring-truncated OSW saponin analogs (1, 18a, and 18b) were synthesized. These greatly simplified trans-hydrindane disaccharides retained considerable inhibitory activity against the growth of HeLa and Jurkat T cells (IC(50)=0.8-21.1 microM).     

Synthesis and biological activities of cyclic ADP-carbocyclic-ribose and its analogs

An efficient synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was achieved. Treatment of N1-carbocyclic-ribosyladenosine bisphosphate derivative 10 with AgNO3 in the presence of molecular sieves 3A in pyridine gave the desired cyclic product in 93% yield, which was deprotected to give the target cyclic ADP-carbocyclic-ribose (2).     

Synthesis and anticancer activities of novel 3,5-disubstituted-1,2,4-oxadiazoles

A series of 3,5-disubstituted-1,2,4-oxadiazoles were synthesized and evaluated for their in vitro anti-proliferative activities against various cancer cell lines. Formation of 1,2,4-oxadiazole ring was accomplished by the reaction of amidoxime with carboxylic acids. The in vitro cytotoxic effects of 3,5-disubstituted-1,2,4-oxadiazoles have been demonstrated across a wide array of tumor cell types and a few compounds exhibited specificity towards pancreatic (3f, 3h, 3j, and 3k) and prostate (3n) cancer cells. Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 3n is the most selective (>450-fold) and compound 3p is the most cytotoxic (10 nM) against prostate cancer cell lines.     

Synthesis and antioxidative activity of structural analogs of vitamin E

Analogues of alpha-tocopherol with modified structure of side isoprenoid chain and chroman nucleus have been synthesised. The influence of chromanol structure on the dynamic of oxidation products formation have been investigated on models of induced and noninduced bulk-phase peroxidation of ethyl linoleate in presence of 2.3.10(-3)-1.2.10(-2) M alpha-tocopherol and the synthesised compounds.     

Synthesis of constrained ceramide analogs and their potent antileukemic activities

Constrained ceramide analogs were designed and synthesized by binding terminal alcohol and amine of ceramide with additional carbonyl functional group as 3-acetyl (3), 3-propionyl (4), 3-benzoyl (5), and 3-hexadecanoyl-4-(1-hydroxyhexadec-2-enyl)-oxazolidin-2-ones (6). Compounds 4 and 5 showed potent antileukemic activities against human leukemia HL-60 cells with good correlation between cell death and DNA fragmentation.     

Synthesis and activities of 9-pyrrolo-9-deoxoerythromycin a analogs

Preparation of novel 9-pyrrolo-9-deoxoerythromycin A analogs from 9-(S) and (R, erythromycylamines by the Clauson-Kass and Wasserman reactions is described. The biological activities of these novel analogs are also reported.     

Synthesis and antitumor activities of 3-modified 2-methoxyestradiol analogs

The syntheses of 2-methoxyestradiol analogs with modifications at the 3-position are described. The analogs were assessed for their antiproliferative, antiangiogenic, and estrogenic activities. Several lead substituents were identified with similar or improved antitumor activities and reduced metabolic liability compared to 2-methoxyestradiol.     

Synthesis and anticancer activity of aminodihydroquinoline analogs: Identification of novel proapoptotic agents

A series of 2-aminodihydroquinoline analogs were synthesized and their in vitro cytotoxicities against metastatic breast adenocarcinoma cell line MDA-MB-231 were tested. Five out of 16 compounds exhibited promising activity and structure–activity relationship revealed major role of dialkylaminoethyl substituents on dihydroquinoline ring for the activity. Two compounds, 5f and 5h, presented cytotoxicity with IC₅₀ values of about 2 μM when the compounds were treated to the cells without serum. The cell proliferation was inhibited mildly when the cells cultured with serum. Flow cytometry analyses showed that those compounds arrested the cells at G2/M checkpoint when the cell cycle is active while they induce apoptosis when the cell growth is restricted due to the absence of growth factors. These results suggest the two novel compounds may have anticancer activity through cell cycle arrest and pro apoptosis mechanism.