Quantitative Structure–Activity Relationships (QSARs) of Pyrimidine Nucleosides as HIV-1 Antiviral Agents

The structural requirements for the antiviral activity of pyrimidine nucleosides against HIV-1 virus was evaluated with the Hansch SAR analysis. Antiviral activity is best related to the hydrophobicity and steric (L and B3) properties of the substituent at the C5 of pyrimidine ring. Further, the antiviral activity is related to B4 of the substituent at position 3' of the sugar ring with a positive slope. The activity of both uracil and cytosine derivatives can be related to their structure by the same equations, which indicates that the SARs are similar in these two groups of congeners. These results suggest that compounds with a small substituent at the 5 position of the pyrimidine ring and a flat substituent at the 3' position of the sugar ring will be the most active compounds against HIV-1 virus.     

Betulinic acid derivatives as anticancer agents: structure activity relationship

Betulinic acid, a pentacyclic triterpene, is widely distributed throughout the tropics. It possesses several biological properties such as anticancer, anti-inflammatory, antiviral, antiseptic, antimalarial, spermicidal, antimicrobial, antileshmanial, antihelmentic and antifeedent activities. However, betulinic acid was highly regarded for its anticancer and anti-HIV activities. Anticancer role of betulinic acid appeared by inducing apoptosis in cells irrespective of their p53 status. Due to high order safety in betulinic acid, a number of structural modifications carried out to improve its potency and efficacy. The C-1, C-2, C-3, C-4, C-20 and C-28 positions are the diversity centers in betulinic acid, and the derivatives resulted on various structural modifications at these positions screened for their anticancer activity. This review presents the structure activity relationship carried out on C-1, C-2, C-3, C-4, C-20, C-28, A-ring, D-ring and E-ring modified betulinic acid derivatives. We have compiled the most active betulinic acid derivatives along with their activity profile in each series. Structure activity relationship studies revealed that C-28 carboxylic acid was essential for the cytotoxicity. The halo substituent at C-2 position in betulinic acid enhanced the cytotoxicity. Though the relation of the cytotoxicity with the nature of substituents at C-3 position could not be generalized but the ester functionality appeared to be a better substituent for enhancing the cytotoxicity. An interesting observation is that the three rings skeleton (A, B and C rings) had played an important role in eliciting anticancer activity, which could be a new molecular skeleton to design new anticancer drugs.     

Novel linked antiviral and antitumor agents related to netropsin and distamycin: synthesis and biological evaluation

A group of oligopeptides have been synthesized which are structurally related to the natural antiviral antitumor antibiotics netropsin and distamycin bearing two such moieties linked by polymethylene bridges. Cytostatic activity against both human and murine tumor cell lines and their in vitro activity against a range of viruses are reported. Enhanced antiviral activity was obtained against vaccinia virus. As a result of the introduction of the polymethylene linkers [( CH2)n, with n = 1, 2, and 6-8], both the antitumor and antivaccinia virus activity was markedly enhanced, relative to that of the parent compounds netropsin and distamycin. The biological activity of these agents is discussed both in terms of their structural differences and in relation to their minor groove binding to duplex DNA.     

HIV-1 neutralization and tumor cell proliferation inhibition in vitro by simplified analogues of pyrido[4,3,2-mn]thiazolo[5,4-b]acridine marine alkaloids.

The antiviral/antitumor marine alkaloid dercitin was used as a lead compound to design analogues with anti-HIV and tumor inhibitory activities. Deletion of structural features contributing to cytotoxicity led to analogues with lowered T-lymphocyte toxicity profiles. One compound, 5, induced complete protection against HIV-1 infectivity in vitro at 12.5 micrograms/mL (38 microM) without T-cell toxicity up to 400 micrograms/mL. Compound 4 and 5 also inhibited the binding of HIV-1 to H-9 lymphocytes. These compounds may exert antiviral activity by a unique dual extracellular and intracellular mode of action--both preventing viral attachment to lymphocytes as well as intercalating with viral nucleic acid. Analogues with higher cytotoxicity such as 2 which retain the thiazole ring of the natural product proved effective in completely inhibiting the cell proliferation of breast, colon, and lung tumor cell lines at 1.5 microM concentration compared to a 70 microM dose level of 5-fluorouracil. A means of molecular separation of antiviral activity from cytotoxicity was thus achieved, and putative pharmacophores for antiviral and antitumor actions of the prototype molecule dercitin have been deduced. The 2-thio-9-acridinone derivatives 4 and 5 represent a new structural type exhibiting activity against HIV in vitro, serving as chemical leads in the design of anti-AIDS agents, while thiazolo[5,4-b]acridines such as 2 provide leads in the drug design of new antitumor agents.     

QSAR of antineoplastics IV: Hansch analysis of N-(7-indolyl)benzenesulfonamides against KB human nasopharynx carcinoma, colon 38 murine adenocarcinoma and P388 murine leukemia cell lines

Hansch analysis of recently reported antitumor activities of novel N-(7-indolyl)benzenesulfonamide derivatives against KB human nasopharynx carcinoma, colon 38 murine adenocarcinoma and P388 murine leukemia cell lines reveals that the pattern of receptor interactions in human KB cells differs from that in murine (colon 38 and P388 leukemia) cells. The latter two activities are autocorrelated and show similar receptor specificity. It seems that two binding sites, one interacting with the indole fragment and another with phenyl fragment of the indolylbenzenesulfonamide compounds, are present on the murine cell receptors (colon 38 and P388 leukemia) while only the latter binding site is active on the human KB cell receptors. For the activity against KB cells, a para-methyl or paramethoxy substituent on the phenyl ring of benzenesulfonamide moiety greatly enhances the activity. For the other two activities, a 3-chloro or 3-cyano substituent on indole nucleus enhances activities, while presence of bulkier meta or para substituent on the phenyl ring decreases activities. Presence of an ortho substituent on the phenyl ring appears to be detrimental for all the three activities. Equations generated by both QSAR and QAAR studies are quite robust as evidenced from cross-validation by 'leave-one-out' technique.     

Mitomycin C analogues with increased metal complexing ability

Twenty-three new mitomycin C analogues designed to have increased metal complexing ability were synthesized and tested against P388 leukemia in mice. Their ability to complex Cu(II) was revealed by the shifts in their UV absorption spectra caused by this metal. One analogue was clearly more active than mitomycin C in the antitumor assay and two others had good activity. Correlation between antitumor activity and Cu(II) complexing ability was ambiguous. The most active compounds were either not complexers or they were complexers limited to the 2-(2-pyridyl)alkyl type substituent on N7. A variety of amino acid substituents on N7 showed only weak antitumor activity.     

Synthesis and antiviral activity of some novel indole-2-carboxylate derivatives

A series of novel indole-2-carboxylate derivatives were synthesized and assayed to determine their in vitro broad-spectrum antiviral activities. The biological results showed that some of the synthesized compounds exhibited potent broad-spectrum antiviral activity. Notably, compound 8f showed the highest SI value (17.1) to Cox B3 virus. Compound 14f showed both potent inhibitory activity against influenza A (IC₅₀=7.53 μmol/L) and the highest SI value (12.1). SAR results showed that the alkyloxy at the 4-position of indole ring was not crucial to the antiviral activities. Incorporation of an acetyl substituent at the amino group disfavored antiviral activity towards RNA viruses.KEY WORDS: Indole-2-carboxylate, Broad-spectrum antiviral activity, DNA and RNA virus, SAR     

Structure-activity relationship of diphenylthiourea antivirals

The dependence between chemical structure and antiviral activity of N,N'-diphenylthioureas is studied by synthesis and testing of model compounds and use of conformational data. The analysis revealed a number of structural features as essential for the antiviral effect: (1) the presence of an intact -NHC(==S)NH- grouping; (2) the presence of a substituent of the XH type (X = O, NH) in the aromatic ring; (3) the distance between these substituents and the sulfur atom in the 6.68-6.75 A range for the active compounds: (4) a trans conformation of the -C(==S)NH-group bound to the substituted phenyl ring. The directed synthesis of compounds satisfying the above requirements yielded the derivative N-phenyl-N'-(m-aminophenyl)thiourea exhibiting a very high antipicornavirus activity in vitro and several other active analogues (four out of seven synthesized). The possible mechanism of interaction between the active diphenylthiourea derivatives and the viral target is discussed.     

Synthesis and antiviral evaluation of 7-<Emphasis Type="Italic">O</Emphasis>-arylmethylquercetin derivatives against SARS-associated coronavirus (SCV) and hepatitis C virus (HCV)

Aryl diketoacid (ADK) is well known for antiviral activity which can be enhanced by introduction of an aromatic arylmethyl substituent. A natural flavonoid quercetin has a 3,5-dihydroxychromone pharmacophore which is in bioisosteric relationship with the 1,3-diketoacid moiety of the ADK. Thus, it was of our interest to test the antiviral activity of the quercetin derivatives with an arylmethyl group attached. In this study, we prepared a series of the 7-O-arylmethylquercetin derivatives with various aromatic substituents and evaluated their antiviral activity against the SARS-associated coronavirus (SARS-CoV, SCV) as well as hepatitis C virus (HCV). Single difference in the aromatic substituent fine-tuned the biological activity of the 7-O-arylmethylquercetin derivatives to result in two different classes of derivatives selectively active against SCV and HCV.     

Synthesis, physicochemical properties, and antitumor activities of analogs of 1-phenyl-3-benzyl-3-methyltriazenes.

To study the effect of substituents on the antitumor activities of analogs of 1-phenyl-3-benzyl-3-methyltriazenes, a series of compounds was designed and synthesized in which the substituent on the 1-phenyl was an electron-withdrawing group and the substituent on the 3-benzyl had a broad range of physicochemical properties. Of the 13 analogs prepared and tested against Sarcoma-180 in the mouse, five showed significant activity. The results were submitted to discriminant analysis to determine structure-activity relationships.     

A pH-stability study of phoslactomycin B and analysis of the acid and base degradation products

Phoslactomycin B (PLM-B), a potent and selective inhibitor of serine threonine phosphatase is of interest for its antitumor, antifungal and antiviral activity. Described herein is an evaluation of the solution stability of phoslactomycin B at various pH and temperature conditions. Phoslactomycin B was produced from a NPI mutant strain of Streptomyces sp. HK-803 and purified by semi-preparative HPLC. A study of PLM-B degradation was carried out in the pH range of 2 approximately 10 at 30 degrees C and 50 degrees C using an HPLC assay. The PLM-B decomposition was observed to exhibit a U-shaped pH profile and demonstrated both acid and base-catalyzed decomposition. The decomposition could be described by the equation kOBS=kH x 10(-PH) + kOH x 10(pH-14) (kH=45 +/- 7 M(-1) h (-1); kOH= 448+/-73 M(-1h)(-1). PLM-B was found to be most stable at pH 6.63. The major acid and base products were separated and purified. Mass spectroscopic and NMR analysis revealed hydrolysis of the alpha, beta-unsaturated lactone provided the major degradation product under base conditions. Two other products in which hydration of the alpha, beta-unsaturated double bond preceded hydrolysis or methanolysis of the lactone were obtained. Under acidic condition MS and NMR analysis revealed that a dehydration step provided a C9-C11 phosphorinane derivative of PLM-B as one of the major products. The remaining acid degradation products were shown to be mixture of various dehydration products containing an additional double bond in central core of the PLM-B carbon skeleton. The major acid and base degradation products had dramatically reduced antifungal activity despite retaining the same structural core.     

一系列新型虫草素衍生物的设计、合成及其抗肿瘤活性研究

本研究合成了一系列6位嘌呤环取代苯磺酰胺基团的虫草素衍生物,并对其进行了抗肿瘤活性研究.我们对虫草素衍生物具有抗肿瘤活性的药效结构部分做了初步探讨.在MDA-MB-231和A549细胞的抗增殖活性实验中,苯环上有4-甲基和4-硝基取代基的化合物活性优于先导化合物.然而,在HeLa细胞的抗增殖活性实验中,4-甲氧基苯、2...     

Plant antitumor agents. 25. Total synthesis and antileukemic activity of ring A substituted camptothecin analogues. Structure-activity correlations

Nineteen racemic ring A substituted analogues of the antitumor agent 20(S)-camptothecin were prepared by total synthesis and evaluated for in vitro cytotoxic activity against KB cell culture and in vivo antileukemic activity against L1210. These compounds bore a wide variety of substituents at C11 designed to confer upon the ring system a broad range of combinations of electronic, steric, and lipophilic effects. A few C10-substituted derivatives as well as C10,C11-disubstituted analogues prepared as part of a concurrent study have also been included for general comparison. With the notable exception of the cyano derivative, the 11-substituted compounds displayed only modest in vitro and in vivo activities, and there was a remarkable insensitivity toward the nature of the substituent. In contrast, the 9- and 10-substituted compounds exhibited a considerably higher level of dose potency and activity both in vitro and in vivo.     

Syntheses and biological activities of 7 beta-methyl steroids

The preparation of 7 beta-methyl-5 alpha-dihydrotestosterone acetate and its 2-thia-A-nor analogue is described. Biological evaluation shows that a 7 beta-Me largely decreases myotrophic-androgenic activity in both 5 alpha-dihydrotestosterone and the 2-thia-A nor analogue. Testing for antitumor activity shows that the reduction in breast tumor weight was not significant for either compound, but the final tumor size in the animals treated with 7 beta-methyl-2-thia-A nor steroid at 10 (mg/kg)/day was significantly reduced. The effects of 7 beta-Me steroids on the various organ weights are also described. The influence of 7 beta-Me substituent on the biological activities of androgens may be mediated through direct interaction of the substituent with the receptor surface in contact with the third dimension of the steroid molecule.     

Synthesis of certain pyrimido[2,1-b]benzothiazole and benzothiazolo[2,3-b]quinazoline derivatives for in vitro antitumor and antiviral activities

Some new pyrimido[2,1-b]benzothiazole and benzothiazolo[2,3-b]quinazoline derivatives have been synthesized and tested for their antitumor and antiviral activities. Among therm, compounds 5c and 8d exhibited a broad spectrum antitumor activity with full panel (MG-MID) median growth inhibition (GI50) of 11.0 and 11.9 mumol/l, respectively. On the other hand, compounds 5c and 5d showed potential activity against Herpes simplex type-1(HSV-1) with 61 and 50% reduction in the viral plaques, respectively. The detailed synthesis, spectroscopic and biological data are reported.     

Design and synthesis of potent C(2)-symmetric diol-based HIV-1 protease inhibitors: effects of fluoro substitution.

Implementation of derivatized carbohydrates as C(2)-symmetric HIV-1 protease inhibitors has previously been reported. With the objective of improving the anti-HIV activity of such compounds, we synthesized a series of fluoro substituted P1/P1' analogues. These compounds were evaluated for antiviral activity toward both wild type and mutant virus. The potency of the analogues in blocking HIV-1 protease was moderate, with K(i) values ranging from 1 to 7 nM. Nonetheless, compared to the parent nonfluorous inhibitors, a majority of the compounds exhibited improved antiviral activity, for example the 3-fluorobenzyl derivative 9b, which had a K(i) value of 7.13 nM and displayed one of the most powerful antiviral activities in the cellular assay of the series. Our results strongly suggest that fluoro substitution can substantially improve antiviral activity. The X-ray crystal structures of two of the fluoro substituted inhibitors (9a and 9f) cocrystallized with HIV-1 protease are discussed.