Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds 16b (IC50, 67.0 nM) and 19b (IC50, 99.2 nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives.A novel type of 10-fluorocamptothecin derivatives with excellent cytotoxicity activity were designed and synthesized.Download high-res image (168KB)Download full-size image

In an effort to discover potent camptothecin-derived antitumor agents, novel camptothecin analogues with sulfonylpiperazinyl motifs at position-7 were designed and synthesized. They were evaluated for in vitro cytotoxicity with the sulforhodamine-B (SRB) method in five types of human tumor cell lines, A-549, MDA-MB-231, KB, KB-VIN and MCF-7. With IC50 values in the low μM to nM level, most of the new analogues showed greater cytotoxicity activity than the reference compounds irinotecan and topotecan. Furthermore, compounds 12l (IC50, 1.2 nM) and 12k (IC50, 20.2 nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that integration of sulfonylpiperazinyl motifs into position-7 of camptothecin is an effective strategy for discovering new potent cytotoxic camptothecin derivatives.Download high-res image (141KB)Download full-size image

In our continuing search for camptothecin (CPT)-derived antitumor drugs, novel 7-substituted CPT derivatives incorporating piperazinyl-sulfonylamidine moieties were designed, synthesized and evaluated for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB, and KB-VIN). All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, and were more potent than irinotecan. Remarkably, most of the compounds exhibited comparable cytotoxicity against the multidrug-resistant (MDR) KB-VIN and parental KB tumor cell lines, while irinotecan lost activity completely against KB-VIN. Especially, compounds 13r and 13p (IC50 0.38 and 0.85 μM, respectively) displayed the greatest cytotoxicity against the MDR KB-VIN cell line and merit further development into preclinical and clinical drug candidates for treating cancer, including MDR phenotype.Download high-res image (73KB)Download full-size image

•20(S)-Sulfonylamidine CPT-derivatives were prepared and tested for cytotoxicity.•Several analogs showed superior cytotoxic activity compared to irinotecan.•Key structural features related to cytotoxicity were identified by SAR analysis.•Compounds 9 and 15c interacted with Topo I-DNA by a different binding mode from CPT.•These compounds are new generation CPT-derived antitumor agents.In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure–activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π–π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity.CPT (green), 9 (magenta), and 15c (blue) in the binding site of DNA-Topo-I.

In our continuing search for camptothecin (CPT)-derived antitumor drugs, novel structurally diverse PEG-based 20(S)-CPT sulfonylamidine derivatives were designed, synthesized via a Cu-multicomponent reaction (MCR), and evaluated for cytotoxicity against four human tumor cell lines (A-549, MDA-MB-231, KB, and KBvin). All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, and were more potent than irinotecan. Significantly, these derivatives exhibited comparable cytotoxicity against KBvin, while irinotecan was less active against this cell line. With a concise efficient synthesis and potent cytotoxic profiles, especially significant activity towards KBvin, these compounds merit further development as a new generation of CPT-derived PEG-conjugated drug candidates.

Twelve novel 20-sulfonylamidine derivatives (9a–9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.

•New spin-labeled podophyllotoxin analogs were prepared and tested for cytotoxicity.•The synthesis used an isocyanide multicomponent coupling reaction.•Potent cytotoxicity was found against A-549, DU-145, KB and KBvin cancer cell lines.•Two compounds (12e, 12h) showed superior potency to etoposide.Spin-labeled podophyllotoxins have elicited widespread interest due to their far superior antitumor activity compared to podophyllotoxin. To extend our prior studies in this research area, we synthesized a new generation of spin-labeled podophyllotoxin analogs via isocyanide multicomponent reactions and evaluated their cytotoxicity against four human cancer cell lines (A-549, DU-145, KB and KBvin). Most of the compounds exhibited potent cytotoxic activity against all four cell lines, notably against the drug resistant KBvin cancer cell line. Among the new analogs, compounds 12e (IC50: 0.60–0.75 μM) and 12h (IC50: 1.12–2.03 μM) showed superior potency to etoposide (IC50: 2.03 to >20 μM), a clinically available anticancer drug. With a concise efficient synthesis and potent cytotoxic profiles, compounds 12e and 12h merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.

Three series of novel sulfonylurea podophyllotoxin derivatives were designed, synthesized, and evaluated for in vitro cytotoxicity against four tumor cell lines (A-549, DU-145, KB and KBvin). Compounds 14c (IC50: 1.41–1.76 μM) and 14e (IC50: 1.72–2.01 μM) showed superior cytotoxic activity compared with etoposide (IC50: 2.03 to >20 μM), a clinically available anticancer drug. Significantly, most of the compounds exhibited comparable cytotoxicity against the drug-resistant tumor cell line KBvin, while etoposide lost activity completely. Preliminary structure–activity relationship (SAR) correlations indicated that the 4′-O-methyl functionality in podophyllotoxin analogues may be essential to maintain cytotoxic activity, while an arylsulfonylurea side chain at podophyllotoxin’s 4β position can significantly improve cytotoxic activity.

In our continuing search for natural product-based spin-labeled antitumor drugs, 20 novel spin-labeled camptothecin derivatives were synthesized via a Cu-catalyzed one pot reaction and evaluated for cytotoxicity against four human tumor cell lines (A-549, MDA-MB-231, KB, and KBvin). Eighteen of the target compounds (9a, 9b, 9d–9k, 9m–9t) exhibited significant in vitro antiproliferative activity against these four tested tumor cell lines. Compounds 9e and 9j (IC50 0.057 and 0.072 μM, respectively) displayed the greatest cytotoxicity against the multidrug-resistant (MDR) KBvin cell line and merit further development into preclinical and clinical drug candidates for treating cancer including MDR phenotype.

A series of novel 7-(N-substituted-methyl)-camptothecin derivatives was designed, synthesized, and evaluated for in vitro cytotoxicity against four human tumor cell lines, A-549, MDA-MB-231, KB, and KBvin. All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, with IC50 values ranging from 0.0023 to 1.11 μM, and were as or more potent than topotecan. Compounds 9d, 9e, and 9r exhibited the highest antiproliferative activity among all prepared derivatives. Furthermore, all of the compounds were more potent than paclitaxel against the multidrug-resistant (MDR) KBvin subline. With a concise efficient synthesis and potent cytotoxic profiles, especially significant activity towards KBvin, compounds 9d, 9e, and 9r merit further development as a new generation of camptothecin-derived anticancer clinical trial candidates.

Oxidative stress imposed by reactive oxygen species plays a crucial role in pathophysiology of inflammatory diseases. In the present study, sesquiterpenoids and diterpenoids isolated from Siegesbeckia pubescens  , a Chinese traditional medicine used to treat arthritis, were evaluated for inhibition of NO production in activated RAW 264.7 macrophages and FMLP/CB induced O2·- generation and elastase release in human neutrophils. In the former assay, sesquiterpenoids were more potent than diterpenoids. The C-4 carbonyl group in the carabrane-type sesquiterpenoid 3 and the C-9 ether linkage in the germacrane sesquiterpene 7 were associated with the enhanced potency. Also, for the active ent  -kaurane type diterpenoids, esterification of 17-OH with isobutyric acid and acetylation of 18-OH affected the inhibition of O2·- generation and elastase release. This report is the first to describe the inhibitory effects on oxidative stress of secondary metabolites from S. pubescens. Its findings suggest that active terpenoids from the herb could be used as lead anti-inflammatory agents.

New 7-acyl camptothecin derivatives were designed and synthesized from camptothecin in a one-pot reaction through a Minisci type-reaction and were evaluated for cytotoxicity against four tumor cell lines, A-549, DU-145, KB, and KB-vin. All of the new compounds showed significant inhibition of human tumor cell growth, with IC50 values ranging from 0.01538 to 13.342 μM. Most of the derivatives were more cytotoxic than irinotecan, and the (7a) and 7-propionyl (7b) analogs exhibited the highest cytotoxic activity against the tumor cell lines tested. This compound class merits further development as anticancer clinical trial candidates.

Three series of novel spin-labeled rotenone derivatives were synthesized and evaluated for cytotoxicity against four tumor cell lines, A-549, DU-145, KB and KBvin. All of the derivatives showed promising in vitro cytotoxic activity against the tumor cell lines tested, with IC50 values ranging from 0.075 to 0.738 μg/mL. Remarkably, all of the compounds were more potent than paclitaxel against KBvin in vitro, and compounds 3a and 3d displayed the highest cytotoxicity against this cell line (IC50 0.075 and 0.092 μg/mL, respectively). Based on the observed cytotoxicity, structure–activity relationships have been described.Three series of novel spin-labeled rotenone derivatives were synthesized and evaluated for cytotoxicity against four tumor cell lines. Compounds 3a and 3d exhibited most the potent cytotoxicity against KBvin cells with IC50 values of 0.075 and 0.092 μg/mL, respectively.

As part of our continuing investigation of azo-flavonoid derivatives as potential anticancer drug candidates, a series of 2-aryl-6,7-methylenedioxyquinolin-4-one analogues was designed and synthesized. The design combined structural features of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-1), a previously discovered compound with potent in vivo antitumor activity, and 2-arylquinolin-4-ones, identified by CoMFA models. The newly synthesized analogues were evaluated for cytotoxicity against seven human cancer cell lines, and structure−activity relationship (SAR) correlations were established. Analogues 1, 37, and 39 showed potent cytotoxicity against different cancer cell lines. Compound 1 demonstrated selective cytotoxicity against Hep 3B (hepatoma) cells. Compound 37 was cytotoxic against HL-60 (leukemia), HCT-116 (colon cancer), Hep 3B (hepatoma), and SK-MEL-5 (melanoma) cells. Compound 39 exhibited broad cytotoxicity against all seven cancer cell lines, with IC50 values between 0.07 and 0.19 μM. Results from mechanism of action studies revealed that these new quinolone derivatives function as antitubulin agents.

Our current studies aimed at developing new potential anti-AIDS drug candidates have focused on the design and synthesis of new DCK analogs with improved molecular water solubility. Based on the structures and biodata of previous DCK analogs, 3D-QSAR studies have been performed which resulted in two reliable computational models, CoMFA and CoMSIA, with r2 values of 0.995 and 0.987, and q2 values of 0.662 and 0.657, respectively. In accord with these 3D-QSAR models, 15 new DCK analogs with polar functional groups at the 3-position were subsequently designed, synthesized, and evaluated against HIV-1 replication in H9 and MT4 cell lines. New DCK analogs 3b, 3c, 4b, 4c, 6a, 7c, and 9a showed promising potency with EC50 values ranging from 0.09 to 0.0002 μM in both assays. Meanwhile, these promising compounds also showed a wide range of predicted log P values from 0.90 to 5.19, which increased the probability of identifying anti-HIV drug candidates from this class of compounds for clinical trials. Furthermore, both experimental and predicted values matched well, corroborating the reliability of the established 3D-QSAR models.

N-Acetylcolchinol methyl ether 1 served as the starting material to prepare the chloroacetamide (3) and epoxide (5) analogues. Both 3 and 5 were potent inhibitors of tubulin polymerization in vitro. Compound 3 was also 4-fold more cytotoxic than colchicine against the 1A9 tumor cell line and showed a unique cross-resistance profile.N-Acetylcolchinol methyl ether 1 served as the starting material to prepare the chloroacetamide (3) and epoxide (5) analogues. Both 3 and 5 were potent inhibitors of tubulin polymerization in vitro.

Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activities. Some simple isoquinoline alkaloids were significantly active in each assay, and may be useful as lead compounds for developing potential chemotherapeutic agents. These compounds include 13 (antimicrobial), 25, 26, and 42 (antimalarial), 13 and 25 (cytotoxic), and 28 and 29 (anti-HIV). A quaternary nitrogen atom of isoquinolium or dihydroisoquinolinium type may contribute to enhanced potency in the first three types of activities. In contrast, anti-HIV activity was found with tetrahydroisoquinoline and 6,7-dihydroxyisoquinolium salts.Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activity. Several simple isoquinoline alkloids were significantly active in each assay and may be useful as lead compounds for developing potential chemotherapeutic agents.

Ru(II)/Ru(III) polypyridyl complexes containing 2,6-(2′-benzimidazolyl)-pyridine or chalcone as co-ligands were synthesized and characterized previously (Mishra, L.; Sinha, R. Indian J. Chem., Sec. A2001, in press. Mishra, L.; Sinha, R. Indian J. Chem., Sec. A, 39A, 2000, 1131). Their interaction with aqueous buffered calf thymus DNA was measured. (Novakova, O.; Kasparkova, J.; Vrana, O.; van Vliet, P. M., Reedijk, J.; Brabec, V., Biochem.34, 1995, 12369 and these results prompted additional screening for anti-HIV (human immunodeficiency virus) activity against DNA replication in H9 lymphocytes and cytotoxic activity against eight tumor cell lines. The most active compounds were 17 in the former assay (EC50 <0.1 μg/mL and TI >23.1) and 3, 8, 10, and 14 in the latter assay, especially selectively against the 1A9 ovarian cancer cell line (IC50=4.1, 3.8, 3.6, and 2.5 μg/mL, respectively).Ru(II)/Ru(III) polypyridyl complexes containing 2,6-(2′-benzimidazolyl)-pyridine or chalcone as co-ligands were evaluated for cytotoxicity and anti-HIV activity.

Thirteen oleanolic acid derivatives were prepared and evaluated for anti-HIV activity in H9 lymphocytes. Saturating the C12–C13 double bond and converting the C17-carboxyl group to an aminomethyl group led to compounds 13–15 and 19–20, respectively, which showed improved anti-HIV activity. Compound 15 was the most potent derivative with EC50=0.0039 μg/mL and TI=3570.Thirteen oleanolic acid derivatives were prepared and evaluated for anti-HIV activity in H9 lymphocytes. Saturating the C12–C13 double bond and converting the C17-carboxyl group to an aminomethyl group led to compounds 13–15 and 19–20, respectively, which showed improved anti-HIV activity. Compound 15 was the most potent derivative with EC50=0.0039 μg/mL and TI=3570.