научная статья по теме ANDROGENIC-ANABOLIC ACTIVITIES OF SOME NEW SYNTHESIZED STEROIDAL PYRANE, PYRIDINE AND THIOPYRIMIDINE DERIVATIVES Химия

Текст научной статьи на тему «ANDROGENIC-ANABOLIC ACTIVITIES OF SOME NEW SYNTHESIZED STEROIDAL PYRANE, PYRIDINE AND THIOPYRIMIDINE DERIVATIVES»

EHOOPrAHH^ECKAa XHMH3, 2014, moM 40, № 5, c. 618-628

ANDROGENIC-ANABOLIC ACTIVITIES OF SOME NEW SYNTHESIZED STEROIDAL PYRANE, PYRIDINE AND THIOPYRIMIDINE DERIVATIVES

© 2014 Mohamed M. Abdalla*, Abd El-Galil E. Amr**, ***, #, Mohamed A. Al-Omar**, Azza A. Hussain****, and Mohamed S. Amer****

*Research Unit, Saco Pharm. Co., 6th October City 11632, Egypt **Pharmaceutical Chemistry Department, Drug Exploration & Development Chair (DEDC), College of Pharmacy,

King Saud University, Riyadh 11451, Saudi Arabia ***Applied Organic Chemistry Department, National Research Center, Dokki, Cairo, Egypt **** Chemistry Department, Faculty of Science, Zagazige University, Zagazige Egypt Received January 28, 2014; in final form, March 3, 2014

In continuation of our previous work, fused steroidal derivatives with pyrane, pyridine, pyrimidine moieties were synthesized and evaluated as androgenic-anabolic agents. Some of the newly synthesized compounds are exhibited pronounced androgenic-anabolic activities.

Keywords: steroidal derivatives, pyranes, pyridines, pyrimidines, androgenic-anabolic activities

DOI: 10.7868/S0132342314050017

INTRODUCTION

In a previous work, we found that certain substituted steroidal derivatives showed androgenic, anabolic, and anti-inflammatory activities [1—6]. The pharmacodynamics of anabolic steroids is unlike peptide hormones. Water-soluble peptide hormones cannot penetrate the fatty cell membrane and only indirectly affect the nucleus of target cells through their interaction with the cell's surface receptors. However, as fat-soluble hormones, anabolic steroids are membrane-permeable and influence the nucleus of cells by direct action. The pharmacodynamics action of anabolic steroids begin when the exogenous hormone penetrates the membrane of the target cell and binds to an androgen receptor located in the cytoplasm of that cell.

From there, the compound hormone-receptor diffuses into the nucleus, where it either alters the expression of genes [7] or activates processes that send signals to other parts of the cell [8]. Different types of anabolic steroids bind to the androgen receptor with different affinities, depending on their chemical structure [9]. Some anabolic steroids such as methandros-tenolone bind weakly to this receptor in vitro, but still exhibit androgenic effects in vivo. The reason for this discrepancy is not known [10]. The effect of anabolic steroids on muscle mass is caused in at least two ways

# Corresponding author (e-mail: aeamr1963@yahoo.com).

[11]: first, they increase the production of proteins; second, they reduce recovery time by blocking the effects of stress hormone cortisol on muscle tissue, so that catabolism of muscle is greatly reduced. It has been hypothesized that this reduction in muscle breakdown may occur through anabolic steroids inhibiting the action of other steroid hormones called glucocorticoids that promote the breakdown of muscles [12]. In view of these observations and as continuation of our previous works in heterocyclic chemistry, we have herein synthesized some new steroidal pyrane, pyridine and thiopyrimidine candidates and tested their androgenic-anabolic activities.

RESULTS AND DISCUSSION

Arylmethylene of 3p-hydroxyandrostan-17-one derivatives (1a—g) were synthesized according to reported procedures [1—4]. Compounds (1a, b) were treated with ethylcyanoacetate, cyanoacetamide or cyanothioacetamide in the presence of sodium ethoxide to give the corresponding pyrano-derivatives (IIa, b), (IIIa, b) and (IVa, b), respectively. Also, arylmethyl-enes (Ia, c) were reacted with malononitrile under the same previous conditions to afford the corresponding pyridine derivatives (Va, b) and (VIa, b), respectively (Scheme 1).

O

HO

HO

-f" R

H

(Va, b)

a, R = H;

b, R = 4-F

HO

H

(Via, b)

a, R = H;

b, R = 4-F

Scheme 1. Synthetic route for compounds (II—VI).

Additionally, compounds (Ia, d, e, f) were condensed with urea, thiourea or guanidine hydrochloride in the presence of sodium ethoxide to give the corresponding pyrimidine derivatives compounds (VIIa, b), (VIIIa—c) and (IXa, b), respectively. Also, arylmethyl-enes (Ia, g) were treated with N-cyanoguanidine under the same previous conditions to afford the corresponding N-cyanoaminopyrimidine derivatives (Xa, b), respectively (Scheme 2).

Finally, compounds (Ia, d) were condensed with acetyl acetone or ethyl acetoacetate in the presence of sodium ethoxide to give the corresponding cyclohex-ene derivatives (XIa, b) and (XIIa, b), respectively (Scheme 3).

Pharmacological Screening Androgenic-Anabolic Activity

The newly synthesized compounds were then pharmacologically screened for their androgenic-anabolic potency on male albino rats. From Tables 1 and 2 the ratio of the mass gained by the levator ani-muscle to the mass gained by the prostate gland was calculated, where the former indicates the anabolic activity and the latter shows the androgenic effect of the tested compounds. It was revealed that all the tested compounds have significant androgenic as well as anabolic effects.

All the tested compounds showed potent anabolic activities. The six member heterocyclic containing two

HO

O

U

h2n nh2

O

A

N NH

(Ia, f)

C2H5OH/Na

HO

-rR

H

(VIIa, b)

a, R = 4-F;

b, R = 4-NO2

O

S

A

-r-R

H (Ia—g)

H a, R = H; b, R = 4-Cl, c, R d, R = 4-Br; e, R = 2-Cl; f, R = 4-NO2; g, R = 2-OCH3

NH

H

4-F

HO

C2H5OH/Na

NH

A

h2n nh2

C2H5OH/Na

(Ie, f) ^

(Ia, g)

HN- -CN HO^^

A-

N ^ N

H

HO

-r-R

H

(Xa, b)

a, R = H;

b, R = 4-OCH3

SH N^N

-rR

H

(VIIIa-c)

a, R = H;

b, R = 4-Br;

c, R = 2-Cl

NH2 ^N

-rR

(IXa, b)

a, R = 2-Cl;

b, R = 4-NO2

Scheme 2. Synthetic route for compounds (VII—X).

heteroatom's fused onto ring D increases the anabolic activities to higher extent more than those containing one hetero atom, while the later more is more active than those of alicyclic fused ring systems because the increasing in the number of atoms available for hydrogen bonding facilitate the agent approach and fitting with the human androgen receptor (hGR) sites in muscle responsible for anabolic activities.

Belonging to six member heterocyclic containing two heteroatom's fused onto ring D pyrimidine were more anabolic active than pyrimidone derivatives and the descending order of anabolic activity of pyrimidine derivatives according to the attached substituent it is NH, NHCH and SH because the more the facile hydrogen bonding one the more the human androgen receptor (hGR) approach and fitting [13].

Regarding —I effects as the size of the halide atom decreases in para position (fluorine atom is the least atomic size while bromine atom is the largest one), the approach and fitting of the agent to receptor increases while in comparison the same chloro substituent in ortho and para position the ortho one hinders the drug approach to the human androgen receptor (hGR) and decreases the anabolic activities.

Belonging to six member heterocyclic containing one heteroatom fused onto ring D pyridines were more anabolic active than pyridones derivatives while the later is more anabolic active than pyrane because pyri-dine can provide many centers for hydrogen bonding with the human androgen receptor (hGR) sites and the same occurred but with less extent with pyridone due to limiter tautomer formation, here also the descending order of anabolic activity of pyridine derivatives according to the attached substituent to it is SH,

O O

Scheme 3. Synthetic route for compounds (XI) and (XII).

one ehoxyl and two etoxyls because the more the facile hydrogen bonding one with less bulky group (one ethoxyl) the more the human androgen receptor (hGR) approach and fitting.

Regarding the alicyclic ring systems the acetyl derivatives which is smaller size than the ethyl ester permit facile the human androgen receptor (hGR) approach and provides higher anabolic activities than it.

The descending anabolic activity according to substituent on aromatic moiety were groups of—I (molecules containing fluorine atom having higher anabolic activities than those containing chlorine atoms and the later ones of higher anabolic activities than molecules containing bromine atoms, regarding the effect of the position of chlorine atoms on the anabolic activities molecules containing chlorine atom in p-position having higher anabolic activities than those containing chlorine atoms in the o-position of the aromatic moiety), H, groups with —M (NO2) and groups of +M (OCH3), this due to the high electron cloud permit drug the human androgen receptor (hGR) approach and facilitate fitting characters.

Acute Toxicity (LD50)

Initially, acute toxicity of the synthesized compounds was assayed by determining their LD50. Interestingly, most compounds were less toxic than the reference drug, The LD50 (rats) was determined by injecting different increasing doses and calculating the dose that killed 50% of the animals.

Table 1. Androgenic-anabolic activity of newly synthesized compounds (II)-(XII)

Comp. No Mass of prostate gland (g)a Mass of levator ani-muscle (g)a Ratiob

Testosterone 0.760 ± 0.004 0.204 ± 0.005 0.27

Control 0.20 ± 0.005 0.18 ± 0.006 —

(IIa) 0.340 ± 0.009 0.439 ± 0.006 1.29

(IIb) 0.330 ± 0.008 0.429 ± 0.005 1.30

(IIIa) 0.234 ± 0.007 2.647 ± 0.006 11.31

(IIIb) 0.234 ± 0.006 0.314 ± 0.007 1.34

(IVa) 0.421 ± 0.004 0.577 ± 0.008 1.37

(IVb) 0.345 ± 0.005 0.480 ± 0.007 1.39

(Va) 0.321 ± 0.008 0.494 ± 0.004 1.54

(Vb) 0.123 ± 0.007 0.191 ± 0.008 1.55

(VIa) 0.345 ± 0.006 0.486 ± 0.006 1.41

(VIb) 0.432 ± 0.009 0.622 ± 0.005 1.44

(VIIa) 0.453 ± 0.005 0.725 ± 0.006 1.60

(VIIb) 0.343 ± 0.006 0.545 ± 0.007 1.59

(VIIIa) 0.234 ± 0.004 0.388 ± 0.004 1.66

(VIIIb) 0.311 ± 0.004 0.532 ± 0.005 1.71

(VIIIc) 0.342 ± 0.004 0.643 ± 0.007 1.88

(IXa) 0.276 ± 0.006 0.444 ± 0.007 2.61

(IXb) 0.321 ± 0.007 0.684 ± 0.008 2.13

(Xa) 0.421 ± 0.006 0.893 ± 0.009 2.12

(Xb) 0.198 ± 0.005 0.394 ± 0.008 1.99

(XIa) 0.360 ± 0.007

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